Abstract
IL-37, the anti-inflammatory cytokine of the IL-1 family, plays several key roles in the regulation of autoimmune diseases. Yet, its role in Hashimoto’s thyroiditis (HT) is not clear. In the present study, we found that, in tissues from HT patients, most of the follicular epithelial cells were positive for both IL-37 and single Ig IL-1-related receptor (SIGIRR) by immunohistochemical staining, while the infiltrating lymphocytes and other inflammatory cells hardly expressed any. Meanwhile, mRNA expression levels of IL-37 in peripheral blood mononuclear cells (PBMC) of HT patients were significantly higher than those in normal controls measured by quantitative real-time PCR. Finally, we studied the possible role of IL-37 in IFN-γ-stimulated rat FRTL-5 cells. The results showed that IL-1β, TNF-α, and MCP-1 mRNA levels were significantly decreased, while the expression of IL-4 mRNA was dramatically up-regulated in IFN-γ-stimulated rat thyroid cell line FRTL-5 pre-treated with IL-37. The current study, for the first time, demonstrated that the IL-37 network is involved in Hashimoto’s thyroiditis, and IL-37 signaling pathway may ameliorate the excessive autoimmune responses in this chronic lymphocytic thyroiditis.
References
Antonelli A, Ferrari SM, Corrado A, Di Domenicantonio A, Fallahi P (2015) Autoimmune thyroid disorders. Autoimmun Rev 14:174–180. https://doi.org/10.1016/j.autrev.2014.10.016
Ballak DB, van Diepen JA, Moschen AR, Jansen HJ, Hijmans A, Groenhof GJ, Leenders F, Bufler P, Boekschoten MV, Muller M et al (2014) IL-37 protects against obesity-induced inflammation and insulin resistance. Nat Commun 5:4711. https://doi.org/10.1038/ncomms5711
Banchereau J, Pascual V, O’Garra A (2012) From IL-2 to IL-37: the expanding spectrum of anti-inflammatory cytokines. Nat Immunol 13:925–931. https://doi.org/10.1038/ni.2406
Caturegli P, De Remigis A, Rose NR (2014) Hashimoto thyroiditis: clinical and diagnostic criteria. Autoimmun Rev 13:391–397. https://doi.org/10.1016/j.autrev.2014.01.007
Chen HM, Fujita M (2015) IL-37: a new player in immune tolerance. Cytokine 72:113–114. https://doi.org/10.1016/j.cyto.2014.11.025
Dinarello CA, Bufler P (2013) Interleukin-37. Semin Immunol 25:466–468. https://doi.org/10.1016/j.smim.2013.10.004
Ehlers M, Schott M (2014) Hashimoto’s thyroiditis and papillary thyroid cancer: are they immunologically linked? Trends Endocrinol Metab 25:656–664. https://doi.org/10.1016/j.tem.2014.09.001
Fehervari Z (2014) IL-37 as an adaptive dampener. Nat Immunol 15:1103. https://doi.org/10.1038/ni.3038
Ji Q, Zeng Q, Huang Y, Shi Y, Lin Y, Lu Z, Meng K, Wu B, Yu K, Chai M et al (2014) Elevated plasma IL-37, IL-18, and IL-18BP concentrations in patients with acute coronary syndrome. Mediat Inflamm 2014:165742. https://doi.org/10.1155/2014/165742
Khan MF, Al-Jameil N, Al-Rashid M, Tabassum H (2015) Thyroid dysfunction: an autoimmune aspect. Int J Clin Exp Med 8(5):6677–6681
Li C, Zhao PW, Sun XG, Che YY, Jiang YF (2013) Elevated levels of cerebrospinal fluid and plasma interleukin-37 in patients with Guillain-Barre syndrome. Mediat Inflamm. https://doi.org/10.1155/2013/639712
Lunding L, Webering S, Vock C, Schroder A, Raedler D, Schaub B, Fehrenbach H, Wegmann M (2015) IL-37 requires IL-18Rα and SIGIRR/IL-1R8 to diminish allergic airway inflammation in mice. Allergy 70:366–373. https://doi.org/10.1111/all.12566
Luo Y, Cai X, Liu S, Wang S, Nold-Petry CA, Nold MF, Bufler P, Norris D, Dinarello CA, Fujita M (2014) Suppression of antigen-specific adaptive immunity by IL-37 via induction of tolerogenic dendritic cells. Proc Natl Acad Sci USA 111:15178–15183. https://doi.org/10.1073/pnas.1416714111
McNamee EN, Masterson JC, Jedlicka P, McManus M, Grenz A, Collins CB, Nold MF, Nold-Petry C, Bufler P, Dinarello CA et al (2011) Interleukin 37 expression protects mice from colitis. Proc Natl Acad Sci USA 108:16711–16716. https://doi.org/10.1073/pnas.1111982108
Moretti S, Bozza S, Oikonomou V, Renga G, Casagrande A, Iannitti RG, Puccetti M, Garlanda C, Kim S, Li S et al (2014) IL-37 inhibits inflammasome activation and disease severity in murine aspergillosis. PLoS Pathog 10:e1004462. https://doi.org/10.1371/journal.ppat.1004462
Nold MF, Nold-Petry CA, Zepp JA, Palmer BE, Bufler P, Dinarello CA (2010) IL-37 is a fundamental inhibitor of innate immunity. Nat Immunol 11:1014–1022. https://doi.org/10.1038/ni.1944
Nold-Petry CA, Lo CY, Rudloff I, Elgass KD, Li S, Gantier MP, Lotz-Havla AS, Gersting SW, Cho SX, Lao JC et al (2015) IL-37 requires the receptors IL-18Ralpha and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction. Nat Immunol 16:354–365. https://doi.org/10.1038/ni.3103
Riva F, Bonavita E, Barbati E, Muzio M, Mantovani A, Garlanda C (2012) TIR8/SIGIRR is an interleukin-1 receptor/Toll like receptor family member with regulatory functions in inflammation and immunity. Front Immunol 3:322. https://doi.org/10.3389/fimmu.2012.00322
Ruggeri RM, Cristani M, Vicchio TM, Alibrandi A, Giovinazzo S, Saija A, Campenni A, Trimarchi F, Gangemi S (2019) Increased serum interleukin-37 (IL-37) levels correlate with oxidative stress parameters in Hashimoto’s thyroiditis. J Endocrinol Invest 42:199–205. https://doi.org/10.1007/s40618-018-0903-3
Santaguida MG, Nardo S, Del Duca SC, Lococo E, Virili C, Gargano L, Lenti L, Centanni M (2011) Increased interleukin-4-positive lymphocytes in patients with Hashimoto’s thyroiditis and concurrent non-endocrine autoimmune disorders. Clin Exp Immunol 165:148–154. https://doi.org/10.1111/j.1365-2249.2011.04419.x
Szabo-Fresnais N, Blondeau JP, Pomerance M (2008) Activation of the cAMP pathway synergistically increases IL-1-induced IL-6 gene expression in FRTL-5 thyroid cells: involvement of AP-1 transcription factors. Mol Cell Endocrinol 284:28–37. https://doi.org/10.1016/j.mce.2007.12.017
Wald D, Qin J, Zhao Z, Qian Y, Naramura M, Tian L, Towne J, Sims JE, Stark GR, Li X (2003) SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling. Nat Immunol 4:920–927. https://doi.org/10.1038/ni968
Weetman AP (2003) Autoimmune thyroid disease: propagation and progression. Eur J Endocrinol 148(1):1–9. https://doi.org/10.1530/eje.0.1480001
Wu B, Meng K, Ji Q, Cheng M, Yu K, Zhao X, Tony H, Liu Y, Zhou Y, Chang C et al (2014) Interleukin-37 ameliorates myocardial ischaemia/reperfusion injury in mice. Clin Exp Immunol 176:438–451. https://doi.org/10.1111/cei.12284
Yang L, Zhang J, Tao J, Lu T (2015) Elevated serum levels of Interleukin-37 are associated with inflammatory cytokines and disease activity in rheumatoid arthritis. APMIS 123:1025–1031. https://doi.org/10.1111/apm.12467
Ye L, Ji L, Wen Z, Zhou Y, Hu D, Li Y, Yu T, Chen B, Zhang J, Ding L et al (2014) IL-37 inhibits the production of inflammatory cytokines in peripheral blood mononuclear cells of patients with systemic lupus erythematosus: its correlation with disease activity. J Transl Med 12:69. https://doi.org/10.1186/1479-5876-12-69
Acknowledgements
This study was supported by two grants from the National Natural Science Foundation of China (81802027 and 81271864) and a grant from Anhui Provincial National Science Foundation (1608085MH173).
Author information
Authors and Affiliations
Corresponding authors
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Ren, CP., Sun, L., Liu, FC. et al. Potential role of IL-37 signaling pathway in feedback regulation of autoimmune Hashimoto thyroiditis. Histochem Cell Biol 152, 467–473 (2019). https://doi.org/10.1007/s00418-019-01820-5
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00418-019-01820-5