Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Extra-adrenal glucocorticoid biosynthesis: implications for autoimmune and inflammatory disorders

Genes & Immunity volume 21, pages 150–168 (2020)Cite this article

Subjects

Abstract

Glucocorticoid synthesis is a complex, multistep process that starts with cholesterol being delivered to the inner membrane of mitochondria by StAR and StAR-related proteins. Here its side chain is cleaved by CYP11A1 producing pregnenolone. Pregnenolone is converted to cortisol by the enzymes 3-βHSD, CYP17A1, CYP21A2, and CYP11B1. Glucocorticoids play a critical role in the regulation of the immune system and exert their action through the glucocorticoid receptor (GR). Although corticosteroids are primarily produced in the adrenal gland, they can also be produced in a number of extra-adrenal tissue including the immune system, skin, brain, and intestine. Glucocorticoid production is regulated by ACTH, CRH, and cytokines such as IL-1, IL-6, and TNFα. The bioavailability of cortisol is also dependent on its interconversion to cortisone, which is inactive, by 11βHSD1/2. Local and systemic glucocorticoid biosynthesis can be stimulated by ultraviolet B, explaining its immunosuppressive activity. In this review, we want to emphasize that dysregulation of extra-adrenal glucocorticoid production can play a key role in a variety of autoimmune diseases including multiple sclerosis (MS), lupus erythematosus (LE), rheumatoid arthritis (RA), and skin inflammatory disorders such as psoriasis and atopic dermatitis (AD). Further research on local glucocorticoid production and its bioavailability may open doors into new therapies for autoimmune diseases.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The biochemical pathway of steroidogenesis.
Fig. 2: The functional organization of the hypothalamic-pituitary-adrenal axis with inputs from the immune system and the skin.
Fig. 3: CYP11A1 expression in human peripheral blood mononuclear cells (PBMCs).
Fig. 4: Expression of StAR and CYP11A1 in HaCaT cells (human epidermal keratinocytes).
Fig. 5

Similar content being viewed by others

References

  1. Miller WL, Auchus RJ. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev. 2011;32:81–151.

    CAS  PubMed  Google Scholar 

  2. Manna PR, Cohen-Tannoudji J, Counis R, Garner CW, Huhtaniemi I, Kraemer FB, et al. Mechanisms of action of hormone-sensitive lipase in mouse Leydig cells: its role in the regulation of the steroidogenic acute regulatory protein. J Biol Chem. 2013;288:8505–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Manna PR, Stetson CL, Slominski AT, Pruitt K. Role of the steroidogenic acute regulatory protein in health and disease. Endocrine. 2016;51:7–21.

    CAS  PubMed  Google Scholar 

  4. Manna PR, Stocco DM. Regulation of the steroidogenic acute regulatory protein expression: functional and physiological consequences. Curr Drug Targets Immune Endocr Metab Disord. 2005;5:93–108.

    CAS  Google Scholar 

  5. Stocco DM, Wang X, Jo Y, Manna PR. Multiple signaling pathways regulating steroidogenesis and steroidogenic acute regulatory protein expression: more complicated than we thought. Mol Endocrinol. 2005;19:2647–59.

    CAS  PubMed  Google Scholar 

  6. Miller WL, Bose HS. Early steps in steroidogenesis: intracellular cholesterol trafficking. J Lipid Res. 2011;52:2111–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Castillo AF, Orlando U, Helfenberger KE, Poderoso C, Podesta EJ. The role of mitochondrial fusion and StAR phosphorylation in the regulation of StAR activity and steroidogenesis. Mol Cell Endocrinol. 2015;408:73–9.

    CAS  PubMed  Google Scholar 

  8. Manna PR, Ahmed AU, Yang S, Narasimhan M, Cohen-Tannoudji J, Slominski AT, et al. Genomic profiling of the steroidogenic acute regulatory protein in breast cancer: in silico assessments and a mechanistic perspective. Cancers (Basel). 2019;11:623.

  9. Clark BJ, Wells J, King SR, Stocco DM. The purification, cloning, and expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR). J Biol Chem. 1994;269:28314–22.

    CAS  PubMed  Google Scholar 

  10. Miller WL. StAR search–what we know about how the steroidogenic acute regulatory protein mediates mitochondrial cholesterol import. Mol Endocrinol. 2007;21:589–601.

    CAS  PubMed  Google Scholar 

  11. Manna PR, Dyson MT, Stocco DM. Regulation of the steroidogenic acute regulatory protein gene expression: present and future perspectives. Mol Hum Reprod. 2009;15:321–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Miller WL. Steroid hormone synthesis in mitochondria. Mol Cell Endocrinol. 2013;379:62–73.

    CAS  PubMed  Google Scholar 

  13. Ascoli M, Fanelli F, Segaloff DL. The lutropin/choriogonadotropin receptor, a 2002 perspective. Endocr Rev. 2002;23:141–74.

    CAS  PubMed  Google Scholar 

  14. Manna PR, Joshi L, Reinhold VN, Aubert ML, Suganuma N, Pettersson K, et al. Synthesis, purification and structural and functional characterization of recombinant form of a common genetic variant of human luteinizing hormone. Hum Mol Genet. 2002;11:301–15.

    CAS  PubMed  Google Scholar 

  15. Hales DB. Testicular macrophage modulation of Leydig cell steroidogenesis. J Reprod Immunol. 2002;57:3–18.

    CAS  PubMed  Google Scholar 

  16. Manna PR, Chandrala SP, Jo Y, Stocco DM. cAMP-independent signaling regulates steroidogenesis in mouse Leydig cells in the absence of StAR phosphorylation. J Mol Endocrinol. 2006;37:81–95.

    CAS  PubMed  Google Scholar 

  17. Manna PR, Dyson MT, Jo Y, Stocco DM. Role of dosage-sensitive sex reversal, adrenal hypoplasia congenita, critical region on the X chromosome, gene 1 in protein kinase A- and protein kinase C-mediated regulation of the steroidogenic acute regulatory protein expression in mouse Leydig tumor cells: mechanism of action. Endocrinology. 2009;150:187–99.

    CAS  PubMed  Google Scholar 

  18. Manna PR, Ahmed AU, Vartak D, Molehin D, Pruitt K. Overexpression of the steroidogenic acute regulatory protein in breast cancer: Regulation by histone deacetylase inhibition. Biochem Biophys Res Commun. 2019;509:476–82.

    CAS  PubMed  Google Scholar 

  19. Manna PR, Stetson CL, Daugherty C, Shimizu I, Syapin PJ, Garrel G, et al. Up-regulation of steroid biosynthesis by retinoid signaling: Implications for aging. Mech Ageing Dev. 2015;150:74–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Manna PR, Stocco DM. Crosstalk of CREB and Fos/Jun on a single cis-element: transcriptional repression of the steroidogenic acute regulatory protein gene. J Mol Endocrinol. 2007;39:261–77.

    CAS  PubMed  Google Scholar 

  21. Manna PR, Dyson MT, Stocco DM. Role of basic leucine zipper proteins in transcriptional regulation of the steroidogenic acute regulatory protein gene. Mol Cell Endocrinol. 2009;302:1–11.

    CAS  PubMed  Google Scholar 

  22. Lavoie HA, King SR. Transcriptional regulation of steroidogenic genes: STARD1, CYP11A1 and HSD3B. Exp Biol Med (Maywood). 2009;234:880–907.

    CAS  Google Scholar 

  23. Bose HS, Sugawara T, Strauss JF,3rd, Miller WL. International Congenital Lipoid Adrenal Hyperplasia Consortium The pathophysiology and genetics of congenital lipoid adrenal hyperplasia. N. Engl J Med. 1996;335:1870–8.

    CAS  PubMed  Google Scholar 

  24. Miller WR. Clinical, pathological, proliferative and molecular responses associated with neoadjuvant aromatase inhibitor treatment in breast cancer. J Steroid Biochem Mol Biol. 2010;118:273–6.

    CAS  PubMed  Google Scholar 

  25. Watari H, Arakane F, Moog-Lutz C, Kallen CB, Tomasetto C, Gerton GL, et al. MLN64 contains a domain with homology to the steroidogenic acute regulatory protein (StAR) that stimulates steroidogenesis. Proc Natl Acad Sci USA. 1997;94:8462–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhang M, Liu P, Dwyer NK, Christenson LK, Fujimoto T, Martinez F, et al. MLN64 mediates mobilization of lysosomal cholesterol to steroidogenic mitochondria. J Biol Chem. 2002;277:33300–10.

    CAS  PubMed  Google Scholar 

  27. Soccio RE, Breslow JL. StAR-related lipid transfer (START) proteins: mediators of intracellular lipid metabolism. J Biol Chem. 2003;278:22183–6.

    CAS  PubMed  Google Scholar 

  28. Strauss JF 3rd, Kishida T, Christenson LK, Fujimoto T, Hiroi H. START domain proteins and the intracellular trafficking of cholesterol in steroidogenic cells. Mol Cell Endocrinol. 2003;202:59–65.

    CAS  PubMed  Google Scholar 

  29. Tuckey RC, Bose HS, Czerwionka I, Miller WL. Molten globule structure and steroidogenic activity of N-218 MLN64 in human placental mitochondria. Endocrinology. 2004;145:1700–7.

    CAS  PubMed  Google Scholar 

  30. Rigotti A, Cohen DE, Zanlungo S. STARTing to understand MLN64 function in cholesterol transport. J Lipid Res. 2010;51:2015–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Mukhin AG, Papadopoulos V, Costa E, Krueger KE. Mitochondrial benzodiazepine receptors regulate steroid biosynthesis. Proc Natl Acad Sci USA. 1989;86:9813–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Krueger KE, Papadopoulos V. Peripheral-type benzodiazepine receptors mediate translocation of cholesterol from outer to inner mitochondrial membranes in adrenocortical cells. J Biol Chem. 1990;265:15015–22.

    CAS  PubMed  Google Scholar 

  33. Papadopoulos V, Mukhin AG, Costa E, Krueger KE. The peripheral-type benzodiazepine receptor is functionally linked to Leydig cell steroidogenesis. J Biol Chem. 1990;265:3772–9.

    CAS  PubMed  Google Scholar 

  34. Papadopoulos V, Amri H, Boujrad N, Cascio C, Culty M, Garnier M, et al. Peripheral benzodiazepine receptor in cholesterol transport and steroidogenesis. Steroids. 1997;62:21–8.

    CAS  PubMed  Google Scholar 

  35. Papadopoulos V, Amri H, Li H, Boujrad N, Vidic B, Garnier M. Targeted disruption of the peripheral-type benzodiazepine receptor gene inhibits steroidogenesis in the R2C Leydig tumor cell line. J Biol Chem. 1997;272:32129–35.

    CAS  PubMed  Google Scholar 

  36. Batarseh A, Papadopoulos V. Regulation of translocator protein 18 kDa (TSPO) expression in health and disease states. Mol Cell Endocrinol. 2010;327:1–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Austin CJ, Kahlert J, Kassiou M, Rendina LM. The translocator protein (TSPO): a novel target for cancer chemotherapy. Int J Biochem Cell Biol. 2013;45:1212–6.

    CAS  PubMed  Google Scholar 

  38. Maaser K, Grabowski P, Sutter AP, Hopfner M, Foss HD, Stein H, et al. Overexpression of the peripheral benzodiazepine receptor is a relevant prognostic factor in stage III colorectal cancer. Clin Cancer Res. 2002;8:3205–9.

    CAS  PubMed  Google Scholar 

  39. Han Z, Junxu, Zhong N. Expression of matrix metalloproteinases MMP-9 within the airways in asthma. Respir Med. 2003;97:563–7.

    CAS  PubMed  Google Scholar 

  40. Galiegue S, Casellas P, Kramar A, Tinel N, Simony-Lafontaine J. Immunohistochemical assessment of the peripheral benzodiazepine receptor in breast cancer and its relationship with survival. Clin Cancer Res. 2004;10:2058–64.

    CAS  PubMed  Google Scholar 

  41. Banati RB, Middleton RJ, Chan R, Hatty CR, Kam WW, Quin C, et al. Positron emission tomography and functional characterization of a complete PBR/TSPO knockout. Nat Commun. 2014;5:5452.

    PubMed  Google Scholar 

  42. Tuckey RC. Progesterone synthesis by the human placenta. Placenta. 2005;26:273–81.

    CAS  PubMed  Google Scholar 

  43. Slominski A, Zjawiony J, Wortsman J, Semak I, Stewart J, Pisarchik A, et al. A novel pathway for sequential transformation of 7-dehydrocholesterol and expression of the P450scc system in mammalian skin. Eur J Biochem. 2004;271:4178–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Slominski A, Semak I, Zjawiony J, Wortsman J, Gandy MN, Li J, et al. Enzymatic metabolism of ergosterol by cytochrome p450scc to biologically active 17alpha,24-dihydroxyergosterol. Chem Biol. 2005;12:931–9.

    CAS  PubMed  Google Scholar 

  45. Slominski A, Semak I, Zjawiony J, Wortsman J, Li W, Szczesniewski A, et al. The cytochrome P450scc system opens an alternate pathway of vitamin D3 metabolism. FEBS J. 2005;272:4080–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Slominski A, Semak I, Wortsman J, Zjawiony J, Li W, Zbytek B, et al. An alternative pathway of vitamin D metabolism. Cytochrome P450scc (CYP11A1)-mediated conversion to 20-hydroxyvitamin D2 and 17,20-dihydroxyvitamin D2. FEBS J. 2006;273:2891–901.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Slominski AT, Kim TK, Chen J, Nguyen MN, Li W, Yates CR, et al. Cytochrome P450scc-dependent metabolism of 7-dehydrocholesterol in placenta and epidermal keratinocytes. Int J Biochem Cell Biol. 2012;44:2003–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Tuckey RC, Slominski AT, Cheng CY, Chen J, Kim TK, Xiao M, et al. Lumisterol is metabolized by CYP11A1: discovery of a new pathway. Int J Biochem Cell Biol. 2014;55:24–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Slominski AT, Kim TK, Li W, Postlethwaite A, Tieu EW, Tang EKY, et al. Detection of novel CYP11A1-derived secosteroids in the human epidermis and serum and pig adrenal gland. Sci Rep. 2015;5:14875.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Lee-Robichaud P, Wright JN, Akhtar ME, Akhtar M. Modulation of the activity of human 17 alpha-hydroxylase-17,20-lyase (CYP17) by cytochrome b5: endocrinological and mechanistic implications. Biochem J. 1995;308(Pt 3):901–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Thomas JL, Myers RP, Strickler RC. Human placental 3 beta-hydroxy-5-ene-steroid dehydrogenase and steroid 5–4-ene-isomerase: purification from mitochondria and kinetic profiles, biophysical characterization of the purified mitochondrial and microsomal enzymes. J Steroid Biochem. 1989;33:209–17.

    CAS  PubMed  Google Scholar 

  52. Phan TS, Merk VM, Brunner T. Extra-adrenal glucocorticoid synthesis at epithelial barriers. Genes Immun. 2019;20:627–640.

    PubMed  Google Scholar 

  53. Sushko TA, Gilep AA, Yantsevich AV, Usanov SA. Role of microsomal steroid hydroxylases in Delta7-steroid biosynthesis. Biochem (Mosc). 2013;78:282–9.

    CAS  Google Scholar 

  54. Slominski AT, Zmijewski MA, Semak I, Sweatman T, Janjetovic Z, Li W, et al. Sequential metabolism of 7-dehydrocholesterol to steroidal 5,7-dienes in adrenal glands and its biological implication in the skin. PloS ONE. 2009;4:e4309.

    PubMed  PubMed Central  Google Scholar 

  55. Guo LW, Wilson WK, Pang J, Shackleton CH. Chemical synthesis of 7- and 8-dehydro derivatives of pregnane-3,17alpha,20-triols, potential steroid metabolites in Smith-Lemli-Opitz syndrome. Steroids. 2003;68:31–42.

    CAS  PubMed  Google Scholar 

  56. Shackleton CH, Roitman E, Kratz LE, Kelley RI. Equine type estrogens produced by a pregnant woman carrying a Smith-Lemli-Opitz syndrome fetus. J Clin Endocrinol Metab. 1999;84:1157–9.

    CAS  PubMed  Google Scholar 

  57. Shackleton CH, Roitman E, Kelley R. Neonatal urinary steroids in Smith-Lemli-Opitz syndrome associated with 7-dehydrocholesterol reductase deficiency. Steroids. 1999;64:481–90.

    CAS  PubMed  Google Scholar 

  58. Shackleton CH, Roitman E, Kratz LE, Kelley RI. Midgestational maternal urine steroid markers of fetal Smith-Lemli-Opitz (SLO) syndrome (7-dehydrocholesterol 7-reductase deficiency). Steroids. 1999;64:446–52.

    CAS  PubMed  Google Scholar 

  59. Holmes MC, Seckl JR. The role of 11beta-hydroxysteroid dehydrogenases in the brain. Mol Cell Endocrinol. 2006;248:9–14.

    CAS  PubMed  Google Scholar 

  60. White PC, Mune T, Agarwal AK. 11 beta-Hydroxysteroid dehydrogenase and the syndrome of apparent mineralocorticoid excess. Endocr Rev. 1997;18:135–56.

    CAS  PubMed  Google Scholar 

  61. Chrousos GP. Stress and disorders of the stress system. Nat Rev Endocrinol. 2009;5:374–81.

    CAS  PubMed  Google Scholar 

  62. Turnbull AV, Rivier CL. Regulation of the hypothalamic-pituitary-adrenal axis by cytokines: actions and mechanisms of action. Physiol Rev. 1999;79:1–71.

    CAS  PubMed  Google Scholar 

  63. Vale W, Spiess J, Rivier C, Rivier J. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science. 1981;213:1394–7.

    CAS  PubMed  Google Scholar 

  64. Slominski A, Wortsman J, Luger T, Paus R, Solomon S. Corticotropin releasing hormone and proopiomelanocortin involvement in the cutaneous response to stress. Physiol Rev. 2000;80:979–1020.

    CAS  PubMed  Google Scholar 

  65. Chan LF, Metherell LA, Clark AJ. Effects of melanocortins on adrenal gland physiology. Eur J Pharm. 2011;660:171–80.

    CAS  Google Scholar 

  66. Clark AJ, Weber A. Adrenocorticotropin insensitivity syndromes. Endocr Rev. 1998;19:828–43.

    CAS  PubMed  Google Scholar 

  67. Keller-Wood M, Shinsako J, Dallman MF. Interaction between stimulus intensity and corticosteroid feedback in control of ACTH. Am J Physiol. 1984;247:E489–94.

    CAS  PubMed  Google Scholar 

  68. Tsigos C, Chrousos GP. Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. J Psychosom Res. 2002;53:865–71.

    PubMed  Google Scholar 

  69. Nappi RE, Rivest S. Stress-induced genetic expression of a selective corticotropin-releasing factor-receptor subtype within the rat ovaries: an effect dependent on the ovulatory cycle. Biol Reprod. 1995;53:1417–28.

    CAS  PubMed  Google Scholar 

  70. Karalis K, Muglia LJ, Bae D, Hilderbrand H, Majzoub JA. CRH and the immune system. J Neuroimmunol. 1997;72:131–6.

    CAS  PubMed  Google Scholar 

  71. Slominski AT, Zmijewski MA, Zbytek B, Tobin DJ, Theoharides TC, Rivier J. Key role of CRF in the skin stress response system. Endocr Rev. 2013;34:827–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Kalantaridou S, Makrigiannakis A, Zoumakis E, Chrousos GP. Peripheral corticotropin-releasing hormone is produced in the immune and reproductive systems: actions, potential roles and clinical implications. Front Biosci. 2007;12:572–80.

    CAS  PubMed  Google Scholar 

  73. Kawahito Y, Sano H, Kawata M, Yuri K, Mukai S, Yamamura Y, et al. Local secretion of corticotropin-releasing hormone by enterochromaffin cells in human colon. Gastroenterology. 1994;106:859–65.

    CAS  PubMed  Google Scholar 

  74. Anton PM, Gay J, Mykoniatis A, Pan A, O’Brien M, Brown D, et al. Corticotropin-releasing hormone (CRH) requirement in Clostridium difficile toxin A-mediated intestinal inflammation. Proc Natl Acad Sci USA. 2004;101:8503–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Zbytek B, Slominski AT. CRH mediates inflammation induced by lipopolysaccharide in human adult epidermal keratinocytes. J Invest Dermatol. 2007;127:730–2.

    CAS  PubMed  Google Scholar 

  76. Karalis K, Sano H, Redwine J, Listwak S, Wilder RL, Chrousos GP. Autocrine or paracrine inflammatory actions of corticotropin-releasing hormone in vivo. Science. 1991;254:421–3.

    CAS  PubMed  Google Scholar 

  77. Slominski A, Zbytek B, Semak I, Sweatman T, Wortsman J. CRH stimulates POMC activity and corticosterone production in dermal fibroblasts. J Neuroimmunol. 2005;162:97–102.

    CAS  PubMed  Google Scholar 

  78. Slominski A, Zbytek B, Szczesniewski A, Semak I, Kaminski J, Sweatman T, et al. CRH stimulation of corticosteroids production in melanocytes is mediated by ACTH. Am J Physiol Endocrinol Metab. 2005;288:E701–6.

    CAS  PubMed  Google Scholar 

  79. Slominski A, Zbytek B, Zmijewski M, Slominski RM, Kauser S, Wortsman J, et al. Corticotropin releasing hormone and the skin. Front Biosci. 2006;11:2230–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Zbytek B, Pfeffer LM, Slominski AT. CRH inhibits NF-kappa B signaling in human melanocytes. Peptides. 2006;27:3276–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Grammatopoulos DK, Ourailidou S. CRH receptor signalling: potential roles in pathophysiology. Curr Mol Pharm. 2017;10:296–310.

    CAS  Google Scholar 

  82. Hillhouse EW, Grammatopoulos DK. The molecular mechanisms underlying the regulation of the biological activity of corticotropin-releasing hormone receptors: implications for physiology and pathophysiology. Endocr Rev. 2006;27:260–86.

    CAS  PubMed  Google Scholar 

  83. Slominski A, Wortsman J, Pisarchik A, Zbytek B, Linton EA, Mazurkiewicz JE, et al. Cutaneous expression of corticotropin-releasing hormone (CRH), urocortin, and CRH receptors. FASEB J. 2001;15:1678–93.

    CAS  PubMed  Google Scholar 

  84. Zhu H, Wang J, Li J, Li S. Corticotropin-releasing factor family and its receptors: pro-inflammatory or anti-inflammatory targets in the periphery? Inflamm Res. 2011;60:715–21.

    CAS  PubMed  Google Scholar 

  85. Zmijewski MA, Slominski AT. Emerging role of alternative splicing of CRF1 receptor in CRF signaling. Acta Biochim Pol. 2010;57:1–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Pisarchik A, Slominski AT. Alternative splicing of CRH-R1 receptors in human and mouse skin: identification of new variants and their differential expression. FASEB J. 2001;15:2754–6.

    CAS  PubMed  Google Scholar 

  87. Grammatopoulos DK, Chrousos GP. Functional characteristics of CRH receptors and potential clinical applications of CRH-receptor antagonists. Trends Endocrinol Metab. 2002;13:436–44.

    CAS  PubMed  Google Scholar 

  88. Slominski A, Roloff B, Curry J, Dahiya M, Szczesniewski A, Wortsman J. The skin produces urocortin. J Clin Endocrinol Metab. 2000;85:815–23.

    CAS  PubMed  Google Scholar 

  89. Castro MG, Morrison E. Post-translational processing of proopiomelanocortin in the pituitary and in the brain. Crit Rev Neurobiol. 1997;11:35–57.

    CAS  PubMed  Google Scholar 

  90. Cone RD, Lu D, Koppula S, Vage DI, Klungland H, Boston B, et al. The melanocortin receptors: agonists, antagonists, and the hormonal control of pigmentation. Recent Prog Horm Res. 1996;51:287–317.

    CAS  PubMed  Google Scholar 

  91. Mountjoy KG, Robbins LS, Mortrud MT, Cone RD. The cloning of a family of genes that encode the melanocortin receptors. Science. 1992;257:1248–51.

    CAS  PubMed  Google Scholar 

  92. Slominski A, Tobin DJ, Shibahara S, Wortsman J. Melanin pigmentation in mammalian skin and its hormonal regulation. Physiol Rev. 2004;84:1155–228.

    CAS  PubMed  Google Scholar 

  93. Blalock JE. The immune system as the sixth sense. J Intern Med. 2005;257:126–38.

    CAS  PubMed  Google Scholar 

  94. Oakley RH, Cidlowski JA. The biology of the glucocorticoid receptor: new signaling mechanisms in health and disease. J Allergy Clin Immunol. 2013;132:1033–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Ramamoorthy S, Cidlowski JA. Corticosteroids: mechanisms of action in health and disease. Rheum Dis Clin North Am. 2016;42:15–31.

    PubMed  PubMed Central  Google Scholar 

  96. Sulaiman RS, Kadmiel M, Cidlowski JA. Glucocorticoid receptor signaling in the eye. Steroids. 2018;133:60–66.

    CAS  PubMed  Google Scholar 

  97. Yamamoto KR. Steroid receptor regulated transcription of specific genes and gene networks. Annu Rev Genet. 1985;19:209–52.

    CAS  PubMed  Google Scholar 

  98. Samarasinghe RA, Witchell SF, DeFranco DB. Cooperativity and complementarity: synergies in non-classical and classical glucocorticoid signaling. Cell Cycle. 2012;11:2819–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Tillery EE, Clements JN, Howard Z. What’s new in multiple sclerosis? Ment Health Clin. 2017;7:213–20.

    PubMed  Google Scholar 

  100. Hemmer B, Nessler S, Zhou D, Kieseier B, Hartung HP. Immunopathogenesis and immunotherapy of multiple sclerosis. Nat Clin Pr Neurol. 2006;2:201–11.

    CAS  Google Scholar 

  101. Luchetti S, van Eden CG, Schuurman K, van Strien ME, Swaab DF, Huitinga I. Gender differences in multiple sclerosis: induction of estrogen signaling in male and progesterone signaling in female lesions. J Neuropathol Exp Neurol. 2014;73:123–35.

    CAS  PubMed  Google Scholar 

  102. Compston A, Coles A. Multiple sclerosis. Lancet. 2002;359:1221–31.

    PubMed  Google Scholar 

  103. Dargahi N, Katsara M, Tselios T, Androutsou ME, de Courten M, Matsoukas J. Multiple sclerosis: immunopathology and treatment update. Brain Sci. 2017;7:pii: E78

    Google Scholar 

  104. Minagar A, Alexander JS. Blood-brain barrier disruption in multiple sclerosis. Mult Scler. 2003;9:540–9.

    CAS  PubMed  Google Scholar 

  105. Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sorensen PS, Thompson AJ, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014;83:278–86.

    PubMed  PubMed Central  Google Scholar 

  106. Mahad DH, Trapp BD, Lassmann H. Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol. 2015;14:183–93.

    CAS  PubMed  Google Scholar 

  107. Maidhof W, Hilas O. Lupus: an overview of the disease and management options. Pharm Ther. 2012;37:240–9.

    Google Scholar 

  108. Cutolo M, Sulli A, Villaggio B, Seriolo B, Accardo S. Relations between steroid hormones and cytokines in rheumatoid arthritis and systemic lupus erythematosus. Ann Rheum Dis. 1998;57:573–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Furie R, Mitrane M, Zhao E, Das M, Li D, Becker PM. Efficacy and tolerability of repository corticotropin injection in patients with persistently active SLE: results of a phase 4, randomised, controlled pilot study. Lupus Sci Med. 2016;3:e000180.

    PubMed  PubMed Central  Google Scholar 

  110. Li J, May W, McMurray RW. Pituitary hormones and systemic lupus erythematosus. Arthritis Rheum. 2005;52:3701–12.

    CAS  PubMed  Google Scholar 

  111. Kuhn A, Bonsmann G, Anders HJ, Herzer P, Tenbrock K, Schneider M. The diagnosis and treatment of systemic lupus erythematosus. Dtsch Arztebl Int. 2015;112:423–32.

    PubMed  PubMed Central  Google Scholar 

  112. Kahlenberg JM, Fox DA. Advances in the medical treatment of rheumatoid arthritis. Hand Clin. 2011;27:11–20.

    PubMed  PubMed Central  Google Scholar 

  113. Guo Q, Wang Y, Xu D, Nossent J, Pavlos NJ, Xu J. Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies. Bone Res. 2018;6:15.

    PubMed  PubMed Central  Google Scholar 

  114. Stuart JM, Postlethwaite AE, Townes AS, Kang AH. Cell-mediated immunity to collagen and collagen alpha chains in rheumatoid arthritis and other rheumatic diseases. Am J Med. 1980;69:13–8.

    CAS  PubMed  Google Scholar 

  115. Watson WC, Cremer MA, Wooley PH, Townes AS. Assessment of the potential pathogenicity of type II collagen autoantibodies in patients with rheumatoid arthritis. Evidence of restricted IgG3 subclass expression and activation of complement C5 to C5a. Arthritis Rheum. 1986;29:1316–21.

    CAS  PubMed  Google Scholar 

  116. Camus P, Fanton A, Bonniaud P, Camus C, Foucher P. Interstitial lung disease induced by drugs and radiation. Respiration. 2004;71:301–26.

    PubMed  Google Scholar 

  117. Fromont A, De Seze J, Fleury MC, Maillefert JF, Moreau T. Inflammatory demyelinating events following treatment with anti-tumor necrosis factor. Cytokine. 2009;45:55–7.

    CAS  PubMed  Google Scholar 

  118. Kerbleski JF, Gottlieb AB. Dermatological complications and safety of anti-TNF treatments. Gut. 2009;58:1033–9.

    CAS  PubMed  Google Scholar 

  119. Ramos-Casals M, Brito-Zeron P, Munoz S, Soria N, Galiana D, Bertolaccini L, et al. Autoimmune diseases induced by TNF-targeted therapies: analysis of 233 cases. Med (Baltim). 2007;86:242–51.

    Google Scholar 

  120. Nalbant S, Ozyurt M, Yildirim M, Kuskucu M. Pulmonary tuberculosis and tuberculous arthritis of knee joint associated with rheumatoid arthritis treated with anti-tumor necrosis factor (TNF)-alpha medication: a case report. Rheumatol Int. 2012;32:2863–6.

    PubMed  Google Scholar 

  121. Liu Y, Krueger JG, Bowcock AM. Psoriasis: genetic associations and immune system changes. Genes Immun. 2007;8:1–12.

    PubMed  Google Scholar 

  122. Parisi R, Symmons DP, Griffiths CE, Ashcroft DM. Identification, management of P et al. global epidemiology of psoriasis: a systematic review of incidence and prevalence. J Invest Dermatol. 2013;133:377–85.

    CAS  PubMed  Google Scholar 

  123. Nestle FO, Di Meglio P, Qin JZ, Nickoloff BJ. Skin immune sentinels in health and disease. Nat Rev Immunol. 2009;9:679–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Huang LH, Zinselmeyer BH, Chang CH, Saunders BT, Elvington A, Baba O, et al. Interleukin-17 drives interstitial entrapment of tissue lipoproteins in experimental psoriasis. Cell Metab. 2019;29:475–487 e7.

    CAS  PubMed  Google Scholar 

  125. Snast I, Reiter O, Atzmony L, Leshem YA, Hodak E, Mimouni D, et al. Psychological stress and psoriasis: a systematic review and meta-analysis. Br J Dermatol. 2018;178:1044–55.

    CAS  PubMed  Google Scholar 

  126. Pietrzak D, Pietrzak A, Grywalska E, Kicinski P, Rolinski J, Donica H, et al. Serum concentrations of interleukin 18 and 25-hydroxyvitamin D3 correlate with depression severity in men with psoriasis. PLoS ONE. 2018;13:e0201589.

    PubMed  PubMed Central  Google Scholar 

  127. Slominski A. On the role of the corticotropin-releasing hormone signalling system in the aetiology of inflammatory skin disorders. Br J Dermatol. 2009;160:229–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Hannen R, Udeh-Momoh C, Upton J, Wright M, Michael A, Gulati A, et al. Dysfunctional skin-derived glucocorticoid synthesis is a pathogenic mechanism of psoriasis. J Invest Dermatol. 2017;137:1630–7.

    CAS  PubMed  Google Scholar 

  129. Slominski AT, Zmijewski MA, Plonka PM, Szaflarski JP, Paus R. How UV light touches the brain and endocrine system through skin, and why. Endocrinology. 2018;159:1992–2007.

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Ronholt K, Iversen L. Old and new biological therapies for psoriasis. Int J Mol Sci. 2017;18:pii: E2297

    Google Scholar 

  131. Damsky W, King BA. JAK inhibitors in dermatology: the promise of a new drug class. J Am Acad Dermatol. 2017;76:736–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Leung DY, Guttman-Yassky E. Deciphering the complexities of atopic dermatitis: shifting paradigms in treatment approaches. J Allergy Clin Immunol. 2014;134:769–79.

    PubMed  PubMed Central  Google Scholar 

  133. Brandt EB, Sivaprasad U. Th2 Cytokines and Atopic Dermatitis. J Clin Cell Immunol. 2011;2:pii: 110.

  134. Jancso N, Jancso-Gabor A, Szolcsanyi J. Direct evidence for neurogenic inflammation and its prevention by denervation and by pretreatment with capsaicin. Br J Pharm Chemother. 1967;31:138–51.

    CAS  Google Scholar 

  135. Basbaum AI, Levine JD. The contribution of the nervous system to inflammation and inflammatory disease. Can J Physiol Pharm. 1991;69:647–51.

    CAS  Google Scholar 

  136. Crofford LJ, Sano H, Karalis K, Friedman TC, Epps HR, Remmers EF, et al. Corticotropin-releasing hormone in synovial fluids and tissues of patients with rheumatoid arthritis and osteoarthritis. J Immunol. 1993;151:1587–96.

    CAS  PubMed  Google Scholar 

  137. Kawahito Y, Sano H, Mukai S, Asai K, Kimura S, Yamamura Y, et al. Corticotropin releasing hormone in colonic mucosa in patients with ulcerative colitis. Gut. 1995;37:544–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Mastorakos G, Bouzas EA, Silver PB, Sartani G, Friedman TC, Chan CC, et al. Immune corticotropin-releasing hormone is present in the eyes of and promotes experimental autoimmune uveoretinitis in rodents. Endocrinology. 1995;136:4650–8.

    CAS  PubMed  Google Scholar 

  139. Seres J, Bornstein SR, Seres P, Willenberg HS, Schulte KM, Scherbaum WA, et al. Corticotropin-releasing hormone system in human adipose tissue. J Clin Endocrinol Metab. 2004;89:965–70.

    CAS  PubMed  Google Scholar 

  140. Devetzis V, Zarogoulidis P, Kakolyris S, Vargemezis V, Chatzaki E. The corticotropin releasing factor system in the kidney: perspectives for novel therapeutic intervention in nephrology. Med Res Rev. 2013;33:847–72.

    CAS  PubMed  Google Scholar 

  141. Paschos KA, Chouridou E, Koureta M, Lambropoulou M, Kolios G, Chatzaki E. The corticotropin releasing factor system in the liver: expression, actions and possible implications in hepatic physiology and pathology. Hormones (Athens). 2013;12:236–45.

    Google Scholar 

  142. Czimmer J, Tache Y. Peripheral corticotropin releasing factor signaling inhibits gastric emptying: mechanisms of action and role in stress-related gastric alterations of motor function. Curr Pharm Des. 2017;23:4042–7.

    CAS  PubMed  Google Scholar 

  143. Hanna-Mitchell AT, Wolf-Johnston A, Roppolo JR, Buffington TC, Birder LA. Corticotropin-releasing factor family peptide signaling in feline bladder urothelial cells. J Endocrinol. 2014;222:113–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Mastorakos G, Webster EL, Friedman TC, Chrousos GP. Immunoreactive corticotropin-releasing hormone and its binding sites in the rat ovary. J Clin Invest. 1993;92:961–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Mastorakos G, Scopa CD, Kao LC, Vryonidou A, Friedman TC, Kattis D, et al. Presence of immunoreactive corticotropin-releasing hormone in human endometrium. J Clin Endocrinol Metab. 1996;81:1046–50.

    CAS  PubMed  Google Scholar 

  146. Bohm M, Apel M, Lowin T, Lorenz J, Jenei-Lanzl Z, Capellino S, et al. Alpha-MSH modulates cell adhesion and inflammatory responses of synovial fibroblasts from osteoarthritis patients. Biochem Pharm. 2016;116:89–99.

    PubMed  Google Scholar 

  147. Lorenz J, Seebach E, Hackmayer G, Greth C, Bauer RJ, Kleinschmidt K, et al. Melanocortin 1 receptor-signaling deficiency results in an articular cartilage phenotype and accelerates pathogenesis of surgically induced murine osteoarthritis. PLoS ONE. 2014;9:e105858.

    PubMed  PubMed Central  Google Scholar 

  148. Bohm M, Grassel S. Role of proopiomelanocortin-derived peptides and their receptors in the osteoarticular system: from basic to translational research. Endocr Rev. 2012;33:623–51.

    PubMed  PubMed Central  Google Scholar 

  149. Slominski A, Paus R, Mazurkiewicz J. Proopiomelanocortin expression in the skin during induced hair growth in mice. Experientia. 1992;48:50–4.

    CAS  PubMed  Google Scholar 

  150. Mazurkiewicz JE, Corliss D, Slominski A. Spatiotemporal expression, distribution, and processing of POMC and POMC-derived peptides in murine skin. J Histochem Cytochem. 2000;48:905–14.

    CAS  PubMed  Google Scholar 

  151. Ermak G, Slominski A. Production of POMC, CRH-R1, MC1, and MC2 receptor mRNA and expression of tyrosinase gene in relation to hair cycle and dexamethasone treatment in the C57BL/6 mouse skin. J Invest Dermatol. 1997;108:160–5.

    CAS  PubMed  Google Scholar 

  152. Miyazaki S, Yoshikawa T, Hashiramoto A, Yamada R, Tsubouchi Y, Kohno M, et al. ACTH expression in synovium of patients with rheumatoid arthritis and Lewis rats with adjuvant arthritis. Mod Rheumatol. 2002;12:206–12.

    CAS  PubMed  Google Scholar 

  153. Smith EM. Neuropeptides as signal molecules in common with leukocytes and the hypothalamic-pituitary-adrenal axis. Brain Behav Immun. 2008;22:3–14.

    CAS  PubMed  Google Scholar 

  154. Koido S, Ohkusa T, Kan S, Takakura K, Saito K, Komita H, et al. Production of corticotropin-releasing factor and urocortin from human monocyte-derived dendritic cells is stimulated by commensal bacteria in intestine. World J Gastroenterol. 2014;20:14420–9.

    PubMed  PubMed Central  Google Scholar 

  155. McEvoy AN, Bresnihan B, FitzGerald O, Murphy EP. Cyclooxygenase 2-derived prostaglandin E2 production by corticotropin-releasing hormone contributes to the activated cAMP response element binding protein content in rheumatoid arthritis synovial tissue. Arthritis Rheum. 2004;50:1132–45.

    CAS  PubMed  Google Scholar 

  156. Leu SJ, Singh VK. Stimulation of interleukin-6 production by corticotropin-releasing factor. Cell Immunol. 1992;143:220–7.

    CAS  PubMed  Google Scholar 

  157. Singh VK, Leu SJ. Enhancing effect of corticotropin-releasing neurohormone on the production of interleukin-1 and interleukin-2. Neurosci Lett. 1990;120:151–4.

    CAS  PubMed  Google Scholar 

  158. Hagan P, Poole S, Bristow AF. Immunosuppressive activity of corticotrophin-releasing factor. Inhibition of interleukin-1 and interleukin-6 production by human mononuclear cells. Biochem J. 1992;281:251–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Singh VK. Stimulatory effect of corticotropin-releasing neurohormone on human lymphocyte proliferation and interleukin-2 receptor expression. J Neuroimmunol. 1989;23:257–62.

    CAS  PubMed  Google Scholar 

  160. Leu SJ, Singh VK. Modulation of natural killer cell-mediated lysis by corticotropin-releasing neurohormone. J Neuroimmunol. 1991;33:253–60.

    CAS  PubMed  Google Scholar 

  161. Kavelaars A, Ballieux RE, Heijnen CJ. The role of IL-1 in the corticotropin-releasing factor and arginine- vasopressin-induced secretion of immunoreactive beta-endorphin by human peripheral blood mononuclear cells. J Immunol. 1989;142:2338–42.

    CAS  PubMed  Google Scholar 

  162. Song JP, Chen X, Yang G, Geng XR. Corticotropin releasing hormone activates CD14(+) cells to induce endothelial barrier dysfunction. Cell Biol Int. 2013. https://doi.org/10.1002/cbin.10133.

  163. Oh SH, Park CO, Wu WH, Kim JY, Jin S, Byamba D. Corticotropin-releasing hormone downregulates IL-10 production by adaptive forkhead box protein 3-negative regulatory T cells in patients with atopic dermatitis. J Allergy Clin Immunol. 2012;129:151–9.

    CAS  PubMed  Google Scholar 

  164. Grammatopoulos DK. Insights into mechanisms of corticotropin-releasing hormone receptor signal transduction. Br J Pharm. 2012;166:85–97.

    CAS  Google Scholar 

  165. Reul JM, Holsboer F. On the role of corticotropin-releasing hormone receptors in anxiety and depression. Dialogues Clin Neurosci. 2002;4:31–46.

    PubMed  PubMed Central  Google Scholar 

  166. Chen AM, Perrin MH, Digruccio MR, Vaughan JM, Brar BK, Arias CM, et al. A soluble mouse brain splice variant of type 2alpha corticotropin-releasing factor (CRF) receptor binds ligands and modulates their activity. Proc Natl Acad Sci USA. 2005;102:2620–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Tsatsanis C, Androulidaki A, Dermitzaki E, Gravanis A, Margioris AN. Corticotropin releasing factor receptor 1 (CRF1) and CRF2 agonists exert an anti-inflammatory effect during the early phase of inflammation suppressing LPS-induced TNF-alpha release from macrophages via induction of COX-2 and PGE2. J Cell Physiol. 2007;210:774–83.

    CAS  PubMed  Google Scholar 

  168. Slominski A, Ermak G, Hwang J, Mazurkiewicz J, Corliss D, Eastman A. The expression of proopiomelanocortin (POMC) and of corticotropin releasing hormone receptor (CRH-R) genes in mouse skin. Biochim Biophys Acta. 1996;1289:247–51.

    PubMed  Google Scholar 

  169. Slominski A, Ermak G, Mazurkiewicz JE, Baker J, Wortsman J. Characterization of corticotropin-releasing hormone (CRH) in human skin. J Clin Endocrinol Metab. 1998;83:1020–4.

    CAS  PubMed  Google Scholar 

  170. Slominski A, Szczesniewski A, Wortsman J. Liquid chromatography-mass spectrometry detection of corticotropin-releasing hormone and proopiomelanocortin-derived peptides in human skin. J Clin Endocrinol Metab. 2000;85:3582–8.

    CAS  PubMed  Google Scholar 

  171. Slominski AT, Roloff B, Zbytek B, Wei ET, Fechner K, Curry J, et al. Corticotropin releasing hormone and related peptides can act as bioregulatory factors in human keratinocytes. Vitr Cell Dev Biol Anim. 2000;36:211–6.

    CAS  Google Scholar 

  172. Quevedo ME, Slominski A, Pinto W, Wei E, Wortsman J. Pleiotropic effects of corticotropin releasing hormone on normal human skin keratinocytes. Vitr Cell Dev Biol Anim. 2001;37:50–4.

    CAS  Google Scholar 

  173. Ito N, Ito T, Betterman A, Paus R. The human hair bulb is a source and target of CRH. J Invest Dermatol. 2004;122:235–7.

    CAS  PubMed  Google Scholar 

  174. Roloff B, Fechner K, Slominski A, Furkert J, Botchkarev VA, Bulfone-Paus S, et al. Hair cycle-dependent expression of corticotropin-releasing factor (CRF) and CRF receptors in murine skin. FASEB J. 1998;12:287–97.

    CAS  PubMed  Google Scholar 

  175. Slominski AT, Botchkarev V, Choudhry M, Fazal N, Fechner K, Furkert J, et al. Cutaneous expression of CRH and CRH-R. Is there a “skin stress response system?”. Ann N Y Acad Sci. 1999;885:287–311.

    CAS  PubMed  Google Scholar 

  176. Ito N, Ito T, Kromminga A, Bettermann A, Takigawa M, Kees F, et al. Human hair follicles display a functional equivalent of the hypothalamic-pituitary-adrenal axis and synthesize cortisol. FASEB J. 2005;19:1332–4.

    CAS  PubMed  Google Scholar 

  177. O’Kane M, Murphy EP, Kirby B. The role of corticotropin-releasing hormone in immune-mediated cutaneous inflammatory disease. Exp Dermatol. 2006;15:143–53.

    PubMed  Google Scholar 

  178. Paus R, Langan EA, Vidali S, Ramot Y, Andersen B. Neuroendocrinology of the hair follicle: principles and clinical perspectives. Trends Mol Med. 2014;20:559–70.

    CAS  PubMed  Google Scholar 

  179. Theoharides TC, Stewart JM, Taracanova A, Conti P, Zouboulis CC. Neuroendocrinology of the skin. Rev Endocr Metab Disord. 2016;17:287–94.

    CAS  PubMed  Google Scholar 

  180. Slominski A, Pisarchik A, Tobin DJ, Mazurkiewicz JE, Wortsman J. Differential expression of a cutaneous corticotropin-releasing hormone system. Endocrinology. 2004;145:941–50.

    CAS  PubMed  Google Scholar 

  181. Zbytek B, Pfeffer LM, Slominski AT. Corticotropin-releasing hormone stimulates NF-kappaB in human epidermal keratinocytes. J Endocrinol. 2004;181:R1-7.

  182. Slominski A, Zbytek B, Pisarchik A, Slominski RM, Zmijewski MA, Wortsman J. CRH functions as a growth factor/cytokine in the skin. J Cell Physiol. 2006;206:780–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Slominski A. POMC gene expression in mouse and hamster melanoma cells. FEBS Lett. 1991;291:165–8.

    CAS  PubMed  Google Scholar 

  184. Slominski A, Wortsman J, Mazurkiewicz JE, Matsuoka L, Dietrich J, Lawrence K, et al. Detection of proopiomelanocortin-derived antigens in normal and pathologic human skin. J Lab Clin Med. 1993;122:658–66.

    CAS  PubMed  Google Scholar 

  185. Schauer E, Trautinger F, Kock A, Schwarz A, Bhardwaj R, Simon M, et al. Proopiomelanocortin-derived peptides are synthesized and released by human keratinocytes. J Clin Invest. 1994;93:2258–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Luger TA, Paus R, Slominski A, Lipton J. The proopiomelanocortin system in cutaneous neuroimmunomodulation. An introductory overview. Annals N Y Acad Sci. 1999;885:xi-xiv.

  187. Talaber G, Jondal M, Okret S. Extra-adrenal glucocorticoid synthesis: immune regulation and aspects on local organ homeostasis. Mol Cell Endocrinol. 2013;380:89–98.

    CAS  PubMed  Google Scholar 

  188. Slominski A, Zbytek B, Nikolakis G, Manna PR, Skobowiat C, Zmijewski M, et al. Steroidogenesis in the skin: implications for local immune functions. J Steroid Biochem Mol Biol. 2013;137:107–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Taves MD, Gomez-Sanchez CE, Soma KK. Extra-adrenal glucocorticoids and mineralocorticoids: evidence for local synthesis, regulation, and function. Am J Physiol Endocrinol Metab. 2011;301:E11–24.

  190. Slominski A, Ermak G, Mihm M. ACTH receptor, CYP11A1, CYP17 and CYP21A2 genes are expressed in skin. J Clin Endocrinol Metab. 1996;81:2746–9.

    CAS  PubMed  Google Scholar 

  191. Thiboutot D, Jabara S, McAllister JM, Sivarajah A, Gilliland K, Cong Z, et al. Human skin is a steroidogenic tissue: steroidogenic enzymes and cofactors are expressed in epidermis, normal sebocytes, and an immortalized sebocyte cell line (SEB-1). J Invest Dermatol. 2003;120:905–14.

    CAS  PubMed  Google Scholar 

  192. Vukelic S, Stojadinovic O, Pastar I, Rabach M, Krzyzanowska A, Lebrun E, et al. Cortisol synthesis in epidermis is induced by IL-1 and tissue injury. J Biol Chem. 2011;286:10265–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Hannen RF, Michael AE, Jaulim A, Bhogal R, Burrin JM, Philpott MP. Steroid synthesis by primary human keratinocytes; implications for skin disease. Biochem Biophys Res Commun. 2011;404:62–7.

    CAS  PubMed  Google Scholar 

  194. Slominski A, Zbytek B, Szczesniewski A, Wortsman J. Cultured human dermal fibroblasts do produce cortisol. J Invest Dermatol. 2006;126:1177–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Skobowiat C, Dowdy JC, Sayre RM, Tuckey RC, Slominski A. Cutaneous hypothalamic-pituitary-adrenal axis homolog: regulation by ultraviolet radiation. Am J Physiol Endocrinol Metab. 2011;301:E484–93.

  196. Skobowiat C, Nejati R, Lu L, Williams RW, Slominski AT. Genetic variation of the cutaneous HPA axis: an analysis of UVB-induced differential responses. Gene. 2013;530:1–7.

    CAS  PubMed  Google Scholar 

  197. Skobowiat C, Sayre RM, Dowdy JC, Slominski AT. Ultraviolet radiation regulates cortisol activity in a waveband-dependent manner in human skin ex vivo. Br J Dermatol. 2013;168:595–601.

    CAS  PubMed  PubMed Central  Google Scholar 

  198. Skobowiat C, Postlethwaite AE, Slominski AT. Skin exposure to ultraviolet b rapidly activates systemic neuroendocrine and immunosuppressive responses. Photochem Photobio. 2017;93:1008–15.

    CAS  Google Scholar 

  199. Slominski AT, Zmijewski MA, Skobowiat C, Zbytek B, Slominski RM, Steketee JD. Sensing the environment: regulation of local and global homeostasis by the skin’s neuroendocrine system. Adv Anat Embryol Cell Biol. 2012;212:1–115.

    Google Scholar 

  200. Wierzbicka JM, Zmijewski MA, Antoniewicz J, Sobjanek M, Slominski AT. Differentiation of keratinocytes modulates skin HPA analog. J Cell Physiol. 2017;232:154–66.

    CAS  PubMed  Google Scholar 

  201. Bigas J, Sevilla LM, Carceller E, Boix J, Perez P. Epidermal glucocorticoid and mineralocorticoid receptors act cooperatively to regulate epidermal development and counteract skin inflammation. Cell Death Dis. 2018;9:588.

    PubMed  PubMed Central  Google Scholar 

  202. Slominski AT, Zmijewski MA. Glucocorticoids inhibit wound healing: novel mechanism of action. J Invest Dermatol. 2017;137:1012–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Jozic I, Vukelic S, Stojadinovic O, Liang L, Ramirez HA, Pastar I, et al. Stress signals, mediated by membranous glucocorticoid receptor, activate PLC/PKC/GSK-3beta/beta-catenin pathway to inhibit wound closure. J Invest Dermatol. 2017;137:1144–54.

    CAS  PubMed  Google Scholar 

  204. Aberg KM, Radek KA, Choi EH, Kim DK, Demerjian M, Hupe M, et al. Psychological stress downregulates epidermal antimicrobial peptide expression and increases severity of cutaneous infections in mice. J Clin Invest. 2007;117:3339–49.

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Slominski A. A nervous breakdown in the skin: stress and the epidermal barrier. J Clin Invest. 2007;117:3166–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  206. Slominski AT, Brozyna AA, Tuckey RC. Cutaneous glucocorticoidogenesis and cortisol signaling are defective in psoriasis. J Invest Dermatol. 2017;137:1609–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Vacchio MS, Papadopoulos V, Ashwell JD. Steroid production in the thymus: implications for thymocyte selection. J Exp Med. 1994;179:1835–46.

    CAS  PubMed  Google Scholar 

  208. Talaber G, Jondal M, Okret S. Local glucocorticoid production in the thymus. Steroids. 2015;103:58–63.

    CAS  PubMed  Google Scholar 

  209. Costa B, Pini S, Gabelloni P, Da Pozzo E, Abelli M, Lari L, et al. The spontaneous Ala147Thr amino acid substitution within the translocator protein influences pregnenolone production in lymphomonocytes of healthy individuals. Endocrinology. 2009;150:5438–45.

    CAS  PubMed  Google Scholar 

  210. Jia Y, Domenico J, Takeda K, Han J, Wang M, Armstrong M, et al. Steroidogenic enzyme Cyp11a1 regulates Type 2 CD8+ T cell skewing in allergic lung disease. Proc Natl Acad Sci USA. 2013;110:8152–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  211. Oka H, Emori Y, Hayashi Y, Nomoto K. Breakdown of Th cell immune responses and steroidogenic CYP11A1 expression in CD4+ T cells in a murine model implanted with B16 melanoma. Cell Immunol. 2000;206:7–15.

    CAS  PubMed  Google Scholar 

  212. Scheinman RI, Cogswell PC, Lofquist AK, Baldwin AS Jr. Role of transcriptional activation of I kappa B alpha in mediation of immunosuppression by glucocorticoids. Science. 1995;270:283–6.

    CAS  PubMed  Google Scholar 

  213. Almawi WY, Beyhum HN, Rahme AA, Rieder MJ. Regulation of cytokine and cytokine receptor expression by glucocorticoids. J Leukoc Biol. 1996;60:563–72.

    CAS  PubMed  Google Scholar 

  214. Auphan N, DiDonato JA, Rosette C, Helmberg A, Karin M. Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis. Science. 1995;270:286–90.

    CAS  PubMed  Google Scholar 

  215. Gottlicher M, Heck S, Herrlich P. Transcriptional cross-talk, the second mode of steroid hormone receptor action. J Mol Med (Berl). 1998;76:480–9.

    CAS  Google Scholar 

  216. Rhen T, Cidlowski JA. Estrogens and glucocorticoids have opposing effects on the amount and latent activity of complement proteins in the rat uterus. Biol Reprod. 2006;74:265–74.

    CAS  PubMed  Google Scholar 

  217. McKay LI, Cidlowski JA. Cross-talk between nuclear factor-kappa B and the steroid hormone receptors: mechanisms of mutual antagonism. Mol Endocrinol. 1998;12:45–56.

    CAS  PubMed  Google Scholar 

  218. Ronchetti S, Migliorati G, Riccardi C. GILZ as a mediator of the anti-inflammatory effects of glucocorticoids. Front Endocrinol (Lausanne). 2015;6:170.

    Google Scholar 

  219. D’Adamio F, Zollo O, Moraca R, Ayroldi E, Bruscoli S, Bartoli A, et al. A new dexamethasone-induced gene of the leucine zipper family protects T lymphocytes from TCR/CD3-activated cell death. Immunity. 1997;7:803–12.

    PubMed  Google Scholar 

  220. Cannarile L, Delfino DV, Adorisio S, Riccardi C, Ayroldi E. Implicating the Role of GILZ in glucocorticoid modulation of T-cell activation. Front Immunol. 2019;10:1823.

    CAS  PubMed  PubMed Central  Google Scholar 

  221. Bereshchenko O, Migliorati G, Bruscoli S, Riccardi C. Glucocorticoid-induced leucine zipper: a novel anti-inflammatory molecule. Front Pharm. 2019;10:308.

    CAS  Google Scholar 

  222. Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids–new mechanisms for old drugs. N. Engl J Med. 2005;353:1711–23.

    CAS  PubMed  Google Scholar 

  223. Fauci AS, Dale DC, Balow JE. Glucocorticosteroid therapy: mechanisms of action and clinical considerations. Ann Intern Med. 1976;84:304–15.

    CAS  PubMed  Google Scholar 

  224. Boumpas DT, Chrousos GP, Wilder RL, Cupps TR, Balow JE. Glucocorticoid therapy for immune-mediated diseases: basic and clinical correlates. Ann Intern Med. 1993;119:1198–208.

    CAS  PubMed  Google Scholar 

  225. Fauci AS, Murakami T, Brandon DD, Loriaux DL, Lipsett MB. Mechanisms of corticosteroid action on lymphocyte subpopulations. VI. Lack of correlation between glucocorticosteroid receptors and the differential effects of glucocorticosteroids on T-cell subpopulations. Cell Immunol. 1980;49:43–50.

    CAS  PubMed  Google Scholar 

  226. Slade JD, Hepburn B. Prednisone-induced alterations of circulating human lymphocyte subsets. J Lab Clin Med. 1983;101:479–87.

    CAS  PubMed  Google Scholar 

  227. Settipane GA, Pudupakkam RK, McGowan JH. Corticosteroid effect on immunoglobulins. J Allergy Clin Immunol. 1978;62:162–6.

    CAS  PubMed  Google Scholar 

  228. Wallen N, Kita H, Weiler D, Gleich GJ. Glucocorticoids inhibit cytokine-mediated eosinophil survival. J Immunol. 1991;147:3490–5.

    CAS  PubMed  Google Scholar 

  229. Andrade MV, Hiragun T, Beaven MA. Dexamethasone suppresses antigen-induced activation of phosphatidylinositol 3-kinase and downstream responses in mast cells. J Immunol. 2004;172:7254–62.

    CAS  PubMed  Google Scholar 

  230. Shodell M, Shah K, Siegal FP. Circulating human plasmacytoid dendritic cells are highly sensitive to corticosteroid administration. Lupus. 2003;12:222–30.

    CAS  PubMed  Google Scholar 

  231. Nikolakis G, Stratakis CA, Kanaki T, Slominski A, Zouboulis CC. Skin steroidogenesis in health and disease. Rev Endocr Metab Disord. 2016;17:247–58.

    CAS  PubMed  Google Scholar 

  232. Slominski AT, Manna PR, Tuckey RC. Cutaneous glucocorticosteroidogenesis: securing local homeostasis and the skin integrity. Exp Dermatol. 2014;23:369–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  233. Sewell WA, Scurr LL, Orphanides H, Kinder S, Ludowyke RI. Induction of interleukin-4 and interleukin-5 expression in mast cells is inhibited by glucocorticoids. Clin Diagn Lab Immunol. 1998;5:18–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  234. Tiala I, Suomela S, Huuhtanen J, Wakkinen J, Holtta-Vuori M, Kainu K, et al. The CCHCR1 (HCR) gene is relevant for skin steroidogenesis and downregulated in cultured psoriatic keratinocytes. J Mol Med (Berl). 2007;85:589–601.

    CAS  Google Scholar 

  235. Sarkar MK, Kaplan N, Tsoi LC, Xing X, Liang Y, Swindell WR, et al. Endogenous glucocorticoid deficiency in psoriasis promotes inflammation and abnormal differentiation. J Invest Dermatol. 2017;137:1474–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  236. Boghozian R, McKenzie BA, Saito LB, Mehta N, Branton WG, Lu J, et al. Suppressed oligodendrocyte steroidogenesis in multiple sclerosis: Implications for regulation of neuroinflammation. Glia. 2017;65:1590–606.

    PubMed  Google Scholar 

  237. Arnason BG, Berkovich R, Catania A, Lisak RP, Zaidi M. Mechanisms of action of adrenocorticotropic hormone and other melanocortins relevant to the clinical management of patients with multiple sclerosis. Mult Scler. 2013;19:130–6.

    PubMed  PubMed Central  Google Scholar 

  238. Miller H, Newell DJ, Ridley A. Multiple sclerosis. Treatment of acute exacerbations with corticotrophin (A.C.T.H.). Lancet. 1961;2:1120–2.

    CAS  PubMed  Google Scholar 

  239. Chatham WW, Kimberly RP. Treatment of lupus with corticosteroids. Lupus. 2001;10:140–7.

    CAS  PubMed  Google Scholar 

  240. Fiechtner JJ, Montroy T. Treatment of moderately to severely active systemic lupus erythematosus with adrenocorticotropic hormone: a single-site, open-label trial. Lupus. 2014;23:905–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  241. Harris-Jones JN. The role of ACTH and cortisone in the treatment of systemic lupus erythematosus. Postgrad Med J. 1956;32:145–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  242. Vogl D, Falk W, Dorner M, Scholmerich J, Straub RH. Serum levels of pregnenolone and 17-hydroxypregnenolone in patients with rheumatoid arthritis and systemic lupus erythematosus: relation to other adrenal hormones. J Rheumatol. 2003;30:269–75.

    CAS  PubMed  Google Scholar 

  243. Straub RH, Cutolo M. Glucocorticoids and chronic inflammation. Rheumatol (Oxf). 2016;55 Suppl 2:ii6–ii14.

    Google Scholar 

  244. Yousri NA, Bayoumy K, Elhaq WG, Mohney RP, Emadi SA, Hammoudeh M, et al. Large scale metabolic profiling identifies novel steroids linked to rheumatoid arthritis. Sci Rep. 2017;7:9137.

    PubMed  PubMed Central  Google Scholar 

  245. Straub RH, Paimela L, Peltomaa R, Scholmerich J, Leirisalo-Repo M. Inadequately low serum levels of steroid hormones in relation to interleukin-6 and tumor necrosis factor in untreated patients with early rheumatoid arthritis and reactive arthritis. Arthritis Rheum. 2002;46:654–62.

    CAS  PubMed  Google Scholar 

  246. Straub RH, Weidler C, Demmel B, Herrmann M, Kees F, Schmidt M, et al. Renal clearance and daily excretion of cortisol and adrenal androgens in patients with rheumatoid arthritis and systemic lupus erythematosus. Ann Rheum Dis. 2004;63:961–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  247. Schlaghecke R, Kornely E, Wollenhaupt J, Specker C. Glucocorticoid receptors in rheumatoid arthritis. Arthritis Rheum. 1992;35:740–4.

    CAS  PubMed  Google Scholar 

  248. Schlaghecke R, Beuscher D, Kornely E, Specker C. Effects of glucocorticoids in rheumatoid arthritis. Diminished glucocorticoid receptors do not result in glucocorticoid resistance. Arthritis Rheum. 1994;37:1127–31.

    CAS  PubMed  Google Scholar 

  249. Edwards C. Sixty years after Hench–corticosteroids and chronic inflammatory disease. J Clin Endocrinol Metab. 2012;97:1443–51.

    CAS  PubMed  Google Scholar 

  250. Axtell RC, de Jong BA, Boniface K, van der Voort LF, Bhat R, De Sarno P, et al. T helper type 1 and 17 cells determine efficacy of interferon-beta in multiple sclerosis and experimental encephalomyelitis. Nat Med. 2010;16:406–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  251. Rowse AL, Naves R, Cashman KS, McGuire DJ, Mbana T, Raman C, et al. Lithium controls central nervous system autoimmunity through modulation of IFN-gamma signaling. PLoS ONE. 2012;7:e52658.

    CAS  PubMed  PubMed Central  Google Scholar 

  252. Mier-Aguilar CA, Cashman KS, Raman C, Soldevila G. CD5-CK2 signaling modulates Erk activation and thymocyte survival. PLoS ONE. 2016;11:e0168155.

    PubMed  PubMed Central  Google Scholar 

  253. Janjetovic Z, Tuckey RC, Nguyen MN, Thorpe EM Jr., Slominski AT. 20,23-dihydroxyvitamin D3, novel P450scc product, stimulates differentiation and inhibits proliferation and NF-kappaB activity in human keratinocytes. J Cell Physiol. 2010;223:36–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  254. Li J, Daly E, Campioli E, Wabitsch M, Papadopoulos V. De novo synthesis of steroids and oxysterols in adipocytes. J Biol Chem. 2014;289:747–64.

    CAS  PubMed  Google Scholar 

  255. MacKenzie SM, Huda SS, Sattar N, Fraser R, Connell JM, Davies E. Depot-specific steroidogenic gene transcription in human adipose tissue. Clin Endocrinol (Oxf). 2008;69:848–54.

    CAS  Google Scholar 

  256. Byeon HR, Lee SH. Expression of steroidogenesis-related genes in rat adipose tissues. Dev Reprod. 2016;20:197–205.

    PubMed  PubMed Central  Google Scholar 

  257. Janssen JM, Bland R, Hewison M, Coughtrie MW, Sharp S, Arts J, et al. Estradiol formation by human osteoblasts via multiple pathways: relation with osteoblast function. J Cell Biochem. 1999;75:528–37.

    CAS  PubMed  Google Scholar 

  258. Rodriguez-Sanz M, Garcia-Giralt N, Prieto-Alhambra D, Servitja S, Balcells S, Pecorelli R, et al. CYP11A1 expression in bone is associated with aromatase inhibitor-related bone loss. J Mol Endocrinol. 2015;55:69–79.

    CAS  PubMed  Google Scholar 

  259. Liu L, Pathak JL, Zhu YQ, Bureik M. Comparison of cytochrome P450 expression in four different human osteoblast models. Biol Chem. 2017;398:1327–34.

    CAS  PubMed  Google Scholar 

  260. Corpechot C, Synguelakis M, Talha S, Axelson M, Sjovall J, Vihko R, et al. Pregnenolone and its sulfate ester in the rat brain. Brain Res. 1983;270:119–25.

    CAS  PubMed  Google Scholar 

  261. Watzka M, Bidlingmaier F, Schramm J, Klingmuller D, Stoffel-Wagner B. Sex- and age-specific differences in human brain CYP11A1 mRNA expression. J Neuroendocrinol. 1999;11:901–5.

    CAS  PubMed  Google Scholar 

  262. Yu L, Romero DG, Gomez-Sanchez CE, Gomez-Sanchez EP. Steroidogenic enzyme gene expression in the human brain. Mol Cell Endocrinol. 2002;190:9–17.

    CAS  PubMed  Google Scholar 

  263. King SR, Manna PR, Ishii T, Syapin PJ, Ginsberg SD, Wilson K, et al. An essential component in steroid synthesis, the steroidogenic acute regulatory protein, is expressed in discrete regions of the brain. J Neurosci. 2002;22:10613–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  264. Lavaque E, Sierra A, Azcoitia I, Garcia-Segura LM. Steroidogenic acute regulatory protein in the brain. Neuroscience. 2006;138:741–7.

    CAS  PubMed  Google Scholar 

  265. Hostettler N, Bianchi P, Gennari-Moser C, Kassahn D, Schoonjans K, Corazza N, et al. Local glucocorticoid production in the mouse lung is induced by immune cell stimulation. Allergy. 2012;67:227–34.

    CAS  PubMed  Google Scholar 

  266. Fernandez-Marcos PJ, Auwerx J, Schoonjans K. Emerging actions of the nuclear receptor LRH-1 in the gut. Biochim Biophys Acta. 2011;1812:947–55.

    CAS  PubMed  Google Scholar 

  267. Noti M, Sidler D, Brunner T. Extra-adrenal glucocorticoid synthesis in the intestinal epithelium: more than a drop in the ocean? Semin Immunopathol. 2009;31:237–48.

    CAS  PubMed  Google Scholar 

  268. Cima I, Corazza N, Dick B, Fuhrer A, Herren S, Jakob S, et al. Intestinal epithelial cells synthesize glucocorticoids and regulate T cell activation. J Exp Med. 2004;200:1635–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  269. Sidler D, Renzulli P, Schnoz C, Berger B, Schneider-Jakob S, Fluck C, et al. Colon cancer cells produce immunoregulatory glucocorticoids. Oncogene. 2011;30:2411–9.

    CAS  PubMed  Google Scholar 

  270. Wang M, Ramirez J, Han J, Jia Y, Domenico J, Seibold MA, et al. The steroidogenic enzyme Cyp11a1 is essential for development of peanut-induced intestinal anaphylaxis. J Allergy Clin Immunol. 2013;132:1174–1183.e8.

    CAS  PubMed  Google Scholar 

  271. Huang SC, Lee CT, Chung BC. Tumor necrosis factor suppresses NR5A2 activity and intestinal glucocorticoid synthesis to sustain chronic colitis. Sci Signal. 2014;7:ra20.

    PubMed  Google Scholar 

  272. Tsai SJ, Wu MH, Lin CC, Sun HS, Chen HM. Regulation of steroidogenic acute regulatory protein expression and progesterone production in endometriotic stromal cells. J Clin Endocrinol Metab. 2001;86:5765–73.

    CAS  PubMed  Google Scholar 

  273. Sugawara T, Nomura E, Fujimoto S. Expression of enzyme associated with steroid hormone synthesis and local production of steroid hormone in endometrial carcinoma cells. J Endocrinol. 2004;180:135–44.

    CAS  PubMed  Google Scholar 

  274. Attar E, Tokunaga H, Imir G, Yilmaz MB, Redwine D, Putman M, et al. Prostaglandin E2 via steroidogenic factor-1 coordinately regulates transcription of steroidogenic genes necessary for estrogen synthesis in endometriosis. J Clin Endocrinol Metab. 2009;94:623–31.

    CAS  PubMed  Google Scholar 

  275. Young MJ, Clyne CD, Cole TJ, Funder JW. Cardiac steroidogenesis in the normal and failing heart. J Clin Endocrinol Metab. 2001;86:5121–6.

    CAS  PubMed  Google Scholar 

  276. Kayes-Wandover KM, White PC. Steroidogenic enzyme gene expression in the human heart. J Clin Endocrinol Metab. 2000;85:2519–25.

    CAS  PubMed  Google Scholar 

  277. Casal AJ, Silvestre JS, Delcayre C, Capponi AM. Expression and modulation of steroidogenic acute regulatory protein messenger ribonucleic acid in rat cardiocytes and after myocardial infarction. Endocrinology. 2003;144:1861–8.

    CAS  PubMed  Google Scholar 

  278. Ohtani T, Mano T, Hikoso S, Sakata Y, Nishio M, Takeda Y, et al. Cardiac steroidogenesis and glucocorticoid in the development of cardiac hypertrophy during the progression to heart failure. J Hypertens. 2009;27:1074–83.

    CAS  PubMed  Google Scholar 

  279. Anuka E, Yivgi-Ohana N, Eimerl S, Garfinkel B, Melamed-Book N, Chepurkol E, et al. Infarct-induced steroidogenic acute regulatory protein: a survival role in cardiac fibroblasts. Mol Endocrinol. 2013;27:1502–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  280. Dalla Valle L, Toffolo V, Vianello S, Belvedere P, Colombo L. Expression of cytochrome P450scc mRNA and protein in the rat kidney from birth to adulthood. J Steroid Biochem Mol Biol. 2004;88:79–89.

    CAS  PubMed  Google Scholar 

  281. Pagotto MA, Roldan ML, Pagotto RM, Lugano MC, Pisani GB, Rogic G, et al. Localization and functional activity of cytochrome P450 side chain cleavage enzyme (CYP11A1) in the adult rat kidney. Mol Cell Endocrinol. 2011;332:253–60.

    CAS  PubMed  Google Scholar 

  282. Provost PR, Tremblay Y. Genes involved in the adrenal pathway of glucocorticoid synthesis are transiently expressed in the developing lung. Endocrinology. 2005;146:2239–45.

    CAS  PubMed  Google Scholar 

  283. Maron BA, Oldham WM, Chan SY, Vargas SO, Arons E, Zhang YY, et al. Upregulation of steroidogenic acute regulatory protein by hypoxia stimulates aldosterone synthesis in pulmonary artery endothelial cells to promote pulmonary vascular fibrosis. Circulation. 2014;130:168–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  284. Ma Y, Ren S, Pandak WM, Li X, Ning Y, Lu C, et al. The effects of inflammatory cytokines on steroidogenic acute regulatory protein expression in macrophages. Inflamm Res. 2007;56:495–501.

    CAS  PubMed  Google Scholar 

  285. Taylor JM, Borthwick F, Bartholomew C, Graham A. Overexpression of steroidogenic acute regulatory protein increases macrophage cholesterol efflux to apolipoprotein AI. Cardiovasc Res. 2010;86:526–34.

    CAS  PubMed  Google Scholar 

  286. Bai Q, Li X, Ning Y, Zhao F, Yin L. Mitochondrial cholesterol transporter, StAR, inhibits human THP-1 monocyte-derived macrophage apoptosis. Lipids. 2010;45:29–36.

    CAS  PubMed  Google Scholar 

  287. Manna PR, Sennoune SR, Martinez-Zaguilan R, Slominski AT, Pruitt K. Regulation of retinoid mediated cholesterol efflux involves liver X receptor activation in mouse macrophages. Biochem Biophys Res Commun. 2015;464:312–7.

    CAS  PubMed  Google Scholar 

  288. Zhou Z, Agarwal VR, Dixit N, White P, Speiser PW. Steroid 21-hydroxylase expression and activity in human lymphocytes. Mol Cell Endocrinol. 1997;127:11–8.

    CAS  PubMed  Google Scholar 

  289. Iscan M, Klaavuniemi T, Coban T, Kapucuoglu N, Pelkonen O, Raunio H. The expression of cytochrome P450 enzymes in human breast tumours and normal breast tissue. Breast Cancer Res Treat. 2001;70:47–54.

    CAS  PubMed  Google Scholar 

  290. Bulun SE, Lin Z, Zhao H, Lu M, Amin S, Reierstad S, et al. Regulation of aromatase expression in breast cancer tissue. Ann N Y Acad Sci. 2009;1155:121–31.

    CAS  PubMed  Google Scholar 

  291. Tuzuner MB, Ozturk T, Eronat AP, Seyhan F, Kisakesen HI, Calay Z, et al. Evaluation of local CYP17A1 and CYP19A1 expression levels as prognostic factors in postmenopausal invasive ductal breast cancer cases. Biochemical Genet. 2016;54:784–802.

    CAS  Google Scholar 

  292. Jun YJ, Park SJ, Hwang JW, Kim TH, Jung KJ, Jung JY, et al. Differential expression of 11beta-hydroxysteroid dehydrogenase type 1 and 2 in mild and moderate/severe persistent allergic nasal mucosa and regulation of their expression by Th2 cytokines: asthma and rhinitis. Clin Exp Allergy. 2014;44:197–211.

    CAS  PubMed  Google Scholar 

  293. Park SJ, Kook JH, Kim HK, Kang SH, Lim SH, Kim HJ, et al. Macrolides increase the expression of 11beta-hydroxysteroid dehydrogenase 1 in human sinonasal epithelium, contributing to glucocorticoid activation in sinonasal mucosa. Br J Pharm. 2015;172:5083–95.

    CAS  Google Scholar 

  294. Baquie M, St-Onge L, Kerr-Conte J, Cobo-Vuilleumier N, Lorenzo PI, Jimenez Moreno CM, et al. The liver receptor homolog-1 (LRH-1) is expressed in human islets and protects {beta}-cells against stress-induced apoptosis. Hum Mol Genet. 2011;20:2823–33.

    CAS  PubMed  Google Scholar 

  295. Morales A, Vilchis F, Chavez B, Morimoto S, Chan C, Robles-Diaz G, et al. Differential expression of steroidogenic factors 1 and 2, cytochrome p450scc, and steroidogenic acute regulatory protein in human pancreas. Pancreas. 2008;37:165–9.

    CAS  PubMed  Google Scholar 

  296. Sakai M, Martinez-Arguelles DB, Aprikian AG, Magliocco AM, Papadopoulos V. De novo steroid biosynthesis in human prostate cell lines and biopsies. Prostate. 2016;76:575–87.

    CAS  PubMed  Google Scholar 

  297. Bennett NC, Hooper JD, Lambie D, Lee CS, Yang T, Vesey DA, et al. Evidence for steroidogenic potential in human prostate cell lines and tissues. Am J Pathol. 2012;181:1078–87.

    CAS  PubMed  Google Scholar 

  298. Cai C, Balk SP. Intratumoral androgen biosynthesis in prostate cancer pathogenesis and response to therapy. Endocr Relat Cancer. 2011;18:R175–82.

    CAS  PubMed  Google Scholar 

  299. Cai C, Chen S, Ng P, Bubley GJ, Nelson PS, Mostaghel EA, et al. Intratumoral de novo steroid synthesis activates androgen receptor in castration-resistant prostate cancer and is upregulated by treatment with CYP17A1 inhibitors. Cancer Res. 2011;71:6503–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  300. Dillard PR, Lin MF, Khan SA. Androgen-independent prostate cancer cells acquire the complete steroidogenic potential of synthesizing testosterone from cholesterol. Mol Cell Endocrinol. 2008;295:115–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  301. Slominski AT, Zmijewski MA, Semak I, Zbytek B, Pisarchik A, Li W, et al. Cytochromes p450 and skin cancer: role of local endocrine pathways. Anticancer Agents Med Chem. 2014;14:77–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  302. Schedel M, Jia Y, Michel S, Takeda K, Domenico J, Joetham A, et al. 1,25D3 prevents CD8+Tc2 skewing and asthma development through VDR binding changes to the Cyp11a1 promoter. Nat Commun. 2016;7:10213.

    CAS  PubMed  PubMed Central  Google Scholar 

  303. Mahata B, Zhang X, Kolodziejczyk AA, Proserpio V, Haim-Vilmovsky L, Taylor AE, et al. Single-cell RNA sequencing reveals T helper cells synthesizing steroids de novo to contribute to immune homeostasis. Cell Rep. 2014;7:1130–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  304. Qiao S, Okret S, Jondal M. Thymocyte-synthesized glucocorticoids play a role in thymocyte homeostasis and are down-regulated by adrenocorticotropic hormone. Endocrinology. 2009;150:4163–9.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The study was supported by NIH grants 1R01AR073004-01A1 and R01AR071189-01A1 and by a VA merit grant (no. 1I01BX004293-01A1) to ATS, internal (UAB) funds to ATS and CR and by the Intramural Research Program of the NIH, the NIEHS, NIH Z01-ES-101585 (to AMJ).

Author information

Authors and Affiliations

  1. Department of Medicine, Division of Rheumatology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    Radomir M. Slominski & Chander Raman

  2. School of Molecular Sciences, The University of Western Australia, Perth, WA, Australia

    Robert C. Tuckey

  3. Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, School of Medicine, Lubbock, TX, 79430, USA

    Pulak R. Manna

  4. Cell Biology Section, Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA

    Anton M. Jetten

  5. Department of Medicine, Division of Rheumatology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA

    Arnold Postlethwaite

  6. VA Medical Center, Memphis, TN, 38163, USA

    Arnold Postlethwaite

  7. Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA

    Andrzej T. Slominski

  8. Comprehensive Cancer Center, Cancer Chemoprevention Program, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    Andrzej T. Slominski

  9. VA Medical Center, Birmingham, AL, 35294, USA

    Andrzej T. Slominski

Authors
  1. Radomir M. Slominski
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert C. Tuckey
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pulak R. Manna
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anton M. Jetten
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Arnold Postlethwaite
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chander Raman
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Andrzej T. Slominski
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andrzej T. Slominski.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Slominski, R.M., Tuckey, R.C., Manna, P.R. et al. Extra-adrenal glucocorticoid biosynthesis: implications for autoimmune and inflammatory disorders. Genes Immun 21, 150–168 (2020). https://doi.org/10.1038/s41435-020-0096-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41435-020-0096-6

This article is cited by

Search

Advanced search

Quick links