Role of interlekin-35 as a biomarker in patients with newly diagnosed Hashimoto’s thyroiditis

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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.

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.

Stathatos N, Daniels GH. Autoimmune thyroid disease. Curr Opin Rheumatol 24, 70-75, 2012.

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.

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