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Interleukin-18-induced cell adhesion molecule expression is associated with feedback regulation by PPAR-γ and NF-κB in Apo E−/− mice

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Abstract

Focal recruitment of monocytes and lymphocytes is one of the earliest detectable cellular responses in atherosclerotic lesion formation. Endothelium may regulate leukocyte recruitment by expressing specific adhesion molecules. Interleukin-18 is a proinflammatory cytokine that plays an important role in vascular pathologies. The present study highlights the modulation of adhesion molecules and PPAR-γ by IL-18 and proposes a novel feedback mechanism by which PPAR-γ may regulate IL-18 expression. Three groups of normal chow diet-fed, male Apo E−/− mice, aged 12 weeks (n = 6/group) were employed: Gp I, phosphate-buffered saline (PBS) (2 mo): Gp II, recombinant IL-18 (rIL-18) (1 mo) followed by PBS (1 mo); Gp III, rIL-18 (1 mo) followed by pyrrolidine dithiocarbamate (PDTC) (1 mo). Significantly augmented mRNA expression of ICAM-1 (~5.7-fold), VCAM-1 (~3.6-fold), and NF-κB (~7-fold) was observed in Gp II mice as compared to Gp I, whereas PPAR-γ expression was not altered. PDTC treatment caused a significant downregulation of ICAM-1 (~4.2-fold), VCAM-1(~2-fold), and NF-κB (~4.5-fold) and upregulation of PPAR-γ expression (~5-fold) in Gp III mice. A similar trend was observed in protein expression. In vivo imaging results demonstrated a marked increase in probe (CF750 dye conjugated to VCAM-1 antibody) fluorescence intensity for VCAM-1 expression in Gp II mice, whereas it was moderately decreased in Gp III. PPAR-γ was found to significantly downregulate both IL-18 levels and IL-18-induced adhesion molecules. The underlying mechanism was found to be via inhibition of NF-κB activity by PDTC, thereby leading to decreased adherence of monocytes to the activated endothelial cells and a step to halt the progression and development of atherosclerotic lesions.

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References

  1. Ross R (1999) Atherosclerosis-an inflammatory disease. N Engl J Med 340:115–126

    Article  CAS  PubMed  Google Scholar 

  2. Frostegård J, Ulfgren AK, Nyberg P, Hedin U, Swedenborg J, Andersson U, Hansson GK (1999) Cytokine expression in advanced human atherosclerotic plaques: dominance of pro-inflammatory (Th1) and macrophage-stimulating cytokines. Atherosclerosis 145:33–43

    Article  PubMed  Google Scholar 

  3. O’Brien KD, Allen MD, McDonald TO, Chait A, Harlan JM, Fishbein D, McCarty J, Ferguson M, Hudkins K, Benjamin CD (1993) Vascular cell adhesion molecule-1 is expressed in human coronary atherosclerotic plaques. Implications for the mode of progression of advanced coronary atherosclerosis. J Clin Invest 92:945–951

    Article  PubMed  PubMed Central  Google Scholar 

  4. Ramos CL, Huo Y, Jung U, Ghosh S, Manka DR, Sarembock IJ, Ley K (1999) Direct demonstration of P-selectin- and VCAM-1-dependent mononuclear cell rolling in early atherosclerotic lesions of apolipoprotein E-deficient mice. Circ Res 84:1237–1244

    Article  CAS  PubMed  Google Scholar 

  5. Oesterling E, Chopra N, Gavalas V et al (2008) Alumina nanoparticles induce expression of endothelial cell adhesion molecules. Toxicol Lett 178:160–166

    Article  CAS  PubMed  Google Scholar 

  6. Mallat Z, Corbaz A, Scoazec A, Besnard S, Lesèche G, Chvatchko Y, Tedgui A (2001) Expression of interleukin-18 in human atherosclerotic plaques and relation to plaque instability. Circulation 104:1598–1603

    Article  CAS  PubMed  Google Scholar 

  7. Oesterling E, Chopra N, Gavalas V, Arzuaga X, Lim EJ, Sultana R, Butterfield DA, Bachas L, Hennig B (2004) Overexpression of IL-18 decreases intimal collagen content and promotes a vulnerable plaque phenotype in apolipoprotein-E-deficient mice. Arterioscler Thromb Vasc Biol 24:2313–2319

    Article  Google Scholar 

  8. Gearing KL, Göttlicher M, Teboul M, Widmark E, Gustafsson JA (1993) Interaction of the peroxisome-proliferator-activated receptor and retinoid X receptor. Proc Natl Acad Sci USA 90:1440–1444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tontonoz P, Nagy L, Alvarez JG, Thomazy VA, Evans RM (1998) PPAR gamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 93:241–252

    Article  CAS  PubMed  Google Scholar 

  10. Chawla A, Boisvert WA, Lee CH, Laffitte BA, Barak Y, Joseph SB, Liao D, Nagy L, Edwards PA, Curtiss LK, Evans RM, Tontonoz P (2001) A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell 7:161–171

    Article  CAS  PubMed  Google Scholar 

  11. Baeuerle PA, Baltimore D (1996) NF-kappa B: ten years after. Cell 87:13–20

    Article  CAS  PubMed  Google Scholar 

  12. Morel JC, Park CC, Woods JM, Koch AE (2001) A novel role for interleukin-18 in adhesion molecule induction through NF-kappa B and phosphatidylinositol (PI) 3-kinase-dependent signal transduction pathways. J Biol Chem 276:37069–37075

    Article  CAS  PubMed  Google Scholar 

  13. Marui N, Offermann MK, Swerlick R, Kunsch C, Rosen CA, Ahmad M, Alexander RW, Medford RM (1993) Vascular cell adhesion molecule-1 (VCAM-1) gene transcription and expression are regulated through an antioxidant-sensitive mechanism in human vascular endothelial cells. J Clin Invest 92:1866–1874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ledebur HC, Parks TP (1995) Transcriptional regulation of the intercellular adhesion molecule-1 gene by inflammatory cytokines in human endothelial cells. Essential roles of a variant NF-kappa B site and p65 homodimers. J Biol Chem 270:933–943

    Article  CAS  PubMed  Google Scholar 

  15. Grandjean-Laquerriere A, Antonicelli F, Gangloff SC, Guenounou M, Le Naour R (2007) UVB-induced IL-18 production in human keratinocyte cell line NCTC 2544 through NF-kappa B activation. Cytokine 37:76–83

    Article  CAS  PubMed  Google Scholar 

  16. Chawla A, Boisvert WA, Lee CH, Laffitte BA, Barak Y, Joseph SB, Liao D, Nagy L, Edwards PA, Curtiss LK, Evans RM, Tontonoz P (2001) A PPAR γ-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell 7:161–171

    Article  CAS  PubMed  Google Scholar 

  17. Repa JJ, Mangelsdorf DJ (2002) The liver X receptor gene team: potential new players in atherosclerosis. Nat Med 8:1243–1248

    Article  CAS  PubMed  Google Scholar 

  18. Silverstein RL (2009) Inflammation, atherosclerosis, and arterial thrombosis: role of the scavenger receptor CD36. Cleve Clin J Med 76:S27–S30

    Article  PubMed  PubMed Central  Google Scholar 

  19. Bhat OM, Kumar PU, Giridharan NV, Kaul D, Kumar MJ, Dhawan V (2014) Interleukin-18-induced atherosclerosis involves CD36 and NF-κB crosstalk in Apo E−/− mice. J Cardiol 66:28–35

    Article  PubMed  Google Scholar 

  20. Chung SW, Kang BY, Kim SH, Pak YK, Cho D, Trinchieri G, Kim TS (2000) Oxidized low-density lipoprotein inhibits interleukin-12 production in lipopolysaccharide-activated mouse macrophages via direct interactions between peroxisome proliferator-activated receptor-gamma and nuclear factor-kappa B. J Biol Chem 275:32681–32687

    Article  CAS  PubMed  Google Scholar 

  21. Piedrahita JA, Zhang SH, Hagaman JR, Oliver PM, Maeda N (1992) Generation of mice carrying a mutant apolipoprotein E gene inactivated by gene targeting in embryonic stem cells. Proc Natl Acad Sci USA 89:4471–4475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Whitman SC, Ravisankar P, Daugherty A (2002) Interleukin-18 enhances atherosclerosis in apolipoprotein E (−/−) mice through the release of interferon-gamma. Circ Res 90:E34–E38

    Article  CAS  PubMed  Google Scholar 

  23. Cuzzocrea S, Chatterjee PK, Mazzon E, Dugo L, Serraino I, Britti D, Mazzullo G, Caputi AP, Thiemermann C (2002) Pyrrolidine dithiocarbamate attenuates the development of acute and chronic inflammation. Br J Pharmacol 135:496–510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wuttge DM, Romert A, Eriksson U, Törmä H, Hansson GK, Sirsjö A (2001) Induction of CD36 by all-trans retinoic acid: retinoic acid receptor signaling in the pathogenesis of atherosclerosis. FASEB J 15:1221–1223

    CAS  PubMed  Google Scholar 

  25. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C (T)) Method. Methods 25:402–408

    Article  CAS  PubMed  Google Scholar 

  26. Katagiri K, Kinashi T, Irie S, Katagiri T (1996) Differential regulation of leukocyte function-associated antigen-1/ intercellular adhesion molecules-1-dependent adhesion and aggregation in HL-60 cells. Blood 87:4276–4285

    CAS  PubMed  Google Scholar 

  27. Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685

    Article  CAS  PubMed  Google Scholar 

  28. Jaffer FA, Libby P, Weissleder R (2006) Molecular and cellular imaging of atherosclerosis: emerging applications. J Am Coll Cardiol 47:1328–1338

    Article  CAS  PubMed  Google Scholar 

  29. Hansson GK, Libby P (2006) The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol 6:508–519

    Article  CAS  PubMed  Google Scholar 

  30. Bernhagen J, Krohn R, Lue H, Gregory JL, Zernecke A, Koenen RR, Dewor M, Georgiev I, Schober A, Leng L, Kooistra T, Fingerle-Rowson G, Ghezzi P, Kleemann R, McColl SR, Bucala R, Hickey MJ, Weber C (2007) MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat Med 13:587–596

    Article  CAS  PubMed  Google Scholar 

  31. Kohka H, Yoshino T, Iwagaki H, Sakuma I, Tanimoto T, Matsuo Y, Kurimoto M, Orita K, Akagi T, Tanaka N (1998) Interleukin-18/interferon-gamma-inducing factor, a novel cytokine, up-regulates ICAM-1 (CD54) expression in KG-1 cells. J Leukoc Biol 64:519–527

    CAS  PubMed  Google Scholar 

  32. Stuyt RJL, Netea MG, Geijtenbeek TBH, Kullberg BJ, Dinarello CA, Van der Meer JWM (2003) Selective regulation of intercellular adhesion molecule-1 expression by interleukin-18 and interleukin-12 on human monocytes. Immunology 110:329–334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Vidal-Vanaclocha F, Fantuzzi G, Mendoza L, Fuentes AM, Anasagasti MJ, Martín J, Carrascal T, Walsh P, Reznikov LL, Kim SH, Novick D, Rubinstein M, Dinarello CA (2000) IL-18 regulates IL-1beta-dependent hepatic melanoma metastasis via vascular cell adhesion molecule-1. Proc Natl Acad Sci USA 97:734–739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Jawien ´ J, Gajda M, Mateuszuk Ł, Olszanecki R, Jakubowski A, Szlachcic A, Korabiowska M, Korbut R (2005) Inhibition of nuclear factor-kB attenuates atherosclerosis in Apo E/LDLR – double knockout mice. J Physiol Pharmacol 56:483–489

    PubMed  Google Scholar 

  35. Liu SF, Ye X, Malik AB (1999) Inhibition of NF-kappaB activation by pyrrolidine dithiocarbamate prevents in vivo expression of proinflammatory genes. Circulation 100:1330–1337

    Article  CAS  PubMed  Google Scholar 

  36. Majdalawieh A, Ro HS (2010) PPARgamma1 and LXR-alpha face a new regulator of macrophage cholesterol homeostasis and inflammatory responsiveness, AEBP1. Nucl Recept Signal 8:e004

    Article  PubMed  PubMed Central  Google Scholar 

  37. Doi T, Sakoda T, Akagami T, Naka T, Mori Y, Tsujino T, Masuyama T, Ohyanagi M (2008) Aldosterone induces interleukin-18 through endothelin-1, angiotensin II, Rho/Rho-kinase, and PPARs in cardiomyocytes. Am J Physiol Heart Circ Physiol 295:H1279–H1287

    Article  CAS  PubMed  Google Scholar 

  38. Alleva DG, Johnson EB, Lio FM, Boehme SA, Conlon PJ, Crowe PD (2002) Regulation of murine macrophage proinflammatory and antiinflammatory cytokines by ligands for peroxisome proliferator-activated receptor-γ: counter-regulatory activity by IFN-γ. J Leukoc Biol 71:677–685

    CAS  PubMed  Google Scholar 

  39. Lehrke M, Lazar MA (2005) The many faces of PPAR-gamma. Cell 123:993–999

    Article  CAS  PubMed  Google Scholar 

  40. Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK (1998) The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature 391:79–82

    Article  CAS  PubMed  Google Scholar 

  41. Takata Y, Kitami Y, Yang ZH, Nakamura M, Okura T, Hiwada K (2002) Vascular inflammation is negatively auto-regulated by interaction between CCAAT/enhancer-binding protein-delta and peroxisome proliferator-activated receptor-gamma. Circ Res 91:427–433

    Article  CAS  PubMed  Google Scholar 

  42. Dinarello CA (1999) IL-18: A TH1-inducing, proinflammatory cytokine and new member of the IL-1 family. J Allergy Clin Immunol 103:11–24

    Article  CAS  PubMed  Google Scholar 

  43. Park KG, Lee KM, Chang YC, Magae J, Ando K, Kim KB, Kim YN, Kim HS, Park JY, Lee KU, Lee IK (2006) The ascochlorin derivative, AS-6, inhibits TNF-alpha-induced adhesion molecule and chemokine expression in rat vascular smooth muscle cells. Life Sci 80:120–126

    Article  CAS  PubMed  Google Scholar 

  44. Libby P (2002) Inflammation in atherosclerosis. Nature 420:868–874

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr. B. Sesikeran, Director, National Institute of Nutrition (NIN), Hyderabad for providing facilities at NIN for carrying out the research work.

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We thank the Department of Biotechnology, New Delhi, India, for providing the financial support.

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Correspondence to Veena Dhawan.

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The animal protocol was approved by the Institute Animal Ethics Committee (IAEC) of PGIMER, Chandigarh (Ref. No. 49/IAEC/227). All the animal procedures were performed following National Institute of Health protocol.

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Bhat, O.M., Uday Kumar, P., Harishankar, N. et al. Interleukin-18-induced cell adhesion molecule expression is associated with feedback regulation by PPAR-γ and NF-κB in Apo E−/− mice. Mol Cell Biochem 428, 119–128 (2017). https://doi.org/10.1007/s11010-016-2922-8

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