Objective. Interleukin-35 (IL-35), an interleukin-12 (IL-12) cytokine family member, is shown to be a potent immunosuppressive and anti-inflammatory cytokine. Inducible regulatory T cells (Tregs) produce IL-35 that mediates the immune inhibitory function of Tregs. Growing evidence revealed that upregulation of IL-35 expression may play a critical role in the prevention of autoimmune diseases in various experimental autoimmunity models and vice versa. Hashimoto’s thyroiditis (HT) is considered to be a Treg cell-related autoimmune disease with loss of self-tolerance.
Methods. One hundred-twenty eight subjects, newly diagnosed hypothyroid HT patients [56 overt (Group 1), 72 subclinical hypothyroid (Group 2)] and 38 healthy controls (Group 3) were enrolled in the study. The levels of serum IL-35 were determined by enzyme-linked immunosorbent assay (ELISA).
Results. Serum IL-35 levels were lower in the HT group when compared with subclinical HT group [304.5 (834.6) pg/ml vs. 636.1 (1542.0) pg/ml, p=0.004] and control cases [304.5 (834.6) pg/ml vs. 1064.7 (2526.8) pg/ml, p<0.001]. Serum IL-35 levels were inversely associated with thyroid stimulating hormone (TSH; rs=-0.396, p<0.001) and anti-thyroid peroxidase antibodies (TPOAb; rs=-0.571, p<0.001) in whole group. Serum IL-35 were negatively associated with TSH (rs=-0.264, p=0.003) and TPOAb (rs=-0.735, p<0.001) in patients with Hashimoto’s thyroiditis (Group 1 + Group 2).
Conclusion. The results suggest that IL-35 may play a role in the pathogenesis of HT.
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Ait-Oufella H Salomon BL Potteaux S Robertson AK Gourdy P Zoll J Merval R Esposito B Cohen JL Fisson S Flavell RA Hansson GK Klatzmann D Tedgui A Mallat Z. Natural regulatory T cells control the development of atherosclerosis in mice. Nat Med 12 178-180 2006.
Akinci B Comlekci A Yener S Bayraktar F Demir T Ozcan MA Yuksel F Yesil S. Hashimoto’s thyroiditis but not treatment of hypothyroidism is associated with altered TGFbeta1 levels. Arch Med Res 39 397-401 2008.
Bettini M Castellaw AH Lennon GP Burton AR Vignali DA. Prevention of autoimmune diabetes by ectopic pancreatic β-cell expression of interleukin-35. Diabetes 61 1519-1526 2012.
Bossowski A Moniuszko M Dąbrowska M Sawicka B Rusak M Jeznach M Wojtowicz J Bodzenta-Lukaszyk A Bossowska A. Lower proportions of CD4+CD25(high) and CD4+FoxP3 but not CD4+CD25+CD127(low) FoxP3+ T cell levels in children with autoimmune thyroid diseases. Autoimmunity 46 222-230 2013.
Caturegli P De Remigis A Rose NR. Hashimoto thyroiditis: clinical and diagnostic criteria. Autoimmun Rev 13 391-397 2014.
Chardes T Chapal N Bresson D Bes C Giudicelli V Lefranc MP Peraldi-Roux S. Th e human anti-thyroid peroxidase autoantibody repertoire in Graves’ and Hashimoto’s autoimmune thyroid diseases. Immunogenetics 54 141-157 2002.
Chaturvedi V Collison LW Guy CS Workman CJ Vignali DA. Cutting edge: Human regulatory T cells require IL-35 to mediate suppression and infectious tolerance. J Immunol 186 6661-6666 2011.
Cogni G Chiovato L. An overview of the pathogenesis of thyroid autoimmunity. Hormones (Athens) 12 19-29 2013.
Collison LW Workman CJ Kuo TT Boyd K Wang Y Vignali KM Cross R Sehy D Blumberg RS Vignali DA. Th e inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450 566-569 2007.
Collison LW Vignali DA. Interleukin-35: odd one out or part of the family? Immunol Rev 226 248-262 2008.
Collison LW Pillai MR Chaturvedi V Vignali DA. Regulatory T cell suppression is potentiated by target T cells in a cell contact IL-35- and IL-10-dependent manner. J Immunol 182 6121-6128 2009.
Collison LW Chaturvedi V Henderson AL Giacomin PR Guy C Bankoti J Finkelstein D Forbes K Workman CJ Brown SA Rehg JE Jones ML Ni HT Artis D Turk MJ Vignali DA. IL-35-mediated induction of a potent regulatory T cell population. Nat Immunol 11 1093-1101 2010.
Effraimidis G Wiersinga WM. Mechanisms in endocrinology: autoimmune thyroid disease: old and new players. Eur J Endocrinol 170 R241-R252 2014.
Fehervari Z Sakaguchi S. CD4+ Tregs and immune control. J Clin Invest 114 1209-1217 2004.
Gangi E Vasu C Cheatem D Prabhakar BS. IL-10-producing CD4+ CD25 + regulatory T cells play a critical role in granulocyte-macrophage colony-stimulating factor-induced suppression of experimental autoimmune thyroiditis. J Immunol 174 7006-7013 2005.
Giordano C Richiusa P Bagnasco M Pizzolanti G Di Blasi F Sbriglia MS Mattina A Pesce G Montagna P Capone F Misiano G Scorsone A Pugliese A Galluzzo A. Differential regulation of Fas-mediated apoptosis in both thyrocyte and lymphocyte cellular compartments correlates with opposite phenotypic manifestations of autoimmune thyroid disease. Thyroid 11 233-244 2001.
Gutekunst R Smolarek H Hasenpusch U et al. Goiter epidemiology: thyroid volume iodine excretion thyroglobulin and thyrotropin in Germany and Sweden. Acta Endocrinol (Copenh) 112 494-501 1986.
Gutekunst R Martin-Teichert H. Requirements for goiter surveys and the determination of thyroid size. In: Iodine Deficiency in Europe. A Continuing Concern. Delange F Dunn JT Glinoer D. Eds. New York: Plenum Press 1993 109-118.
Jacobson EM Tomer Y. Th e genetic basis of thyroid autoimmunity. Thyroid 17 949-961 2007.
Kochetkova I Golden S Holderness K Callis G Pascual DW. IL-35 stimulation of CD39+ regulatory T cells confers protection against collagen II-induced arthritis via the production of IL-10. J Immunol 184 7144-7153 2010.
Lewis E Braverman RD. Werner & Ingbar’s the thyroid: a fundamental and clinical text (10th ed.). Philadelphia: Lippincott Williams & Wilkins. Chapter 4B Kopp P 48-74 2013.
Nicholl MB Ledgewood CL Chen X Bai Q Qin C Cook KM Herrick EJ Diaz-Arias A Moore BJ Fang Y. IL-35 promotes pancreas cancer growth through enhancement of proliferation and inhibition of apoptosis: evidence for a role as an autocrine growth factor. Cytokine 70 126-133 2014.
Niedbala W Wei XQ Cai B Hueber AJ Leung BP McInnes IB Liew FY. IL-35 is a novel cytokine with therapeutic effects against collagen-induced arthritis through the expansion of regulatory T cells and suppression of Th 17 cells. Eur J Immunol 37 3021-3029 2007.
Olson BM Sullivan JA Burlingham WJ. Interleukin 35: key mediator of suppression and the propagation of infectious tolerance. Front Immunol 4 315 2013.
Pellerin L Jenks JA Begin P Bacchetta R Nadeau KC. Regulatory T cells and their roles in immune dysregulation and allergy. Immunol Res 58 358-368 2014.
Shevach EM. Mechanisms of foxp3 + T regulatory cell mediated suppression. Immunity 30 636-645 2009.
Stojanovic J Srefanovic D Vulovic D Puskas L Markovic L. Role of apoptosis in pathogenesis of thyroiditis. Med Pregl 62 49-52 2009.
Vural P Degirmencioglu S Erden S Gelincik A. Th e relationship between transforming growth factor-beta1 vascular endothelial growth factor nitric oxide and Hashimoto’s thyroiditis. Int Immunopharmacol 9 212-215 2009.
Wang SH Chen GH Fan Y Van Antwerp M Baker JR Jr. Tumor necrosis factor-related apoptosis-inducing ligand inhibits experimental autoimmune thyroiditis by the expansion of CD4 + CD25 + regulatory T cells. Endocrinology 150 2000-2007 2009.
Wang RX Yu CR Dambuza IM Mahdi RM Dolinska MB Sergeev YV Wingfield PT Kim SH Egwuagu CE. Interleukin-35 induces regulatory B cells that suppress autoimmune disease. Nat Med 20 633-641 2014.
Whitehead GS Wilson RH Nakano K Burch LH Nakano H Cook DN. IL-35 production by inducible costimulator (ICOS)-positive regulatory T cells reverses established IL-17-dependent allergic airways disease. J Allergy Clin Immunol 129 207-215.e1-5 2012.
Wirtz S Billmeier U McHedlidze T Blumberg RS Neurath MF. Interleukin-35 Mediates Mucosal Immune Responses that Protect Against T Cell-Dependent Colitis. Gastroenterology 141 1875-1886 2011.
Yu S Fang Y Sharp GC Braley-Mullen H. Transgenic expression of TGF-beta on thyrocytes inhibits development of spontaneous autoimmune thyroiditis and increases regulatory T cells in thyroids of NOD.H-2h4 mice. J Immunol 184 5352-5359 2010.