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06.05.2020 | Original Article—Liver, Pancreas, and Biliary Tract

Interleukin-35 promotes the differentiation of regulatory T cells and suppresses Th2 response in IgG4-related type 1 autoimmune pancreatitis

verfasst von: Takashi Ito, Toshihiro Tanaka, Koh Nakamaru, Takashi Tomiyama, Takashi Yamaguchi, Yugo Ando, Tsukasa Ikeura, Toshiro Fukui, Kazushige Uchida, Akiyoshi Nishio, Kazuichi Okazaki

Erschienen in: Journal of Gastroenterology | Ausgabe 8/2020

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Abstract

Background

IgG4-related disease (IgG4-RD) is a systemic inflammatory disease, which includes type 1 autoimmune pancreatitis (AIP). Interleukin-35 (IL-35) exhibits immunosuppressive effects in several autoimmune diseases. However, the expression of IL-35 had not been reported so far in type 1 AIP. We evaluated the association between IL-35 and several cytokines, which mediate the function of Tregs in type 1 AIP.

Methods

Plasma was collected from patients with type 1 AIP, alcoholic chronic pancreatitis (ACP), and healthy controls (HC) and assayed for cytokine expression. Total mRNA separated from peripheral blood was isolated from naïve Tregs (nTregs) and effector Tregs (eTregs). EBI3 and IL-12p35 gene expressions were tested in these cells by quantitative PCR. In addition, expression of IL-35 subunits in the pancreatic tissues of patients with type 1 AIP and ACP was analyzed by immunohistochemistry.

Results

IL-35 was significantly elevated in type 1 AIP (n = 32) plasma compared with ACP (n = 16) and HC (n = 22), but IL-27 was not. We also detected many cells expressing both EBI3 and IL-12p35 in type 1 AIP tissues. Moreover, in peripheral blood lymphocyte, the percentage of nTregs and eTregs of CD4⁺ T cells in patients with type 1 AIP (n = 14) compared with HC (n = 15) was significantly decreased and increased, respectively. There were no significant differences of gene expression in patients with type 1 AIP and HC.

Conclusions

This study identified elevated expression of plasma IL-35 and tissue IL-35 subunits in patients with type 1 AIP. This might lead to inflammation suppression via activated eTregs. IL-35 might be associated with this anti-inflammatory role, especially against the Th2 response through several cytokines and the differentiation of Tregs in type 1 AIP.

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Okazaki K, Kawa S, Kamisawa T, et al. Amendment of the Japanese Consensus Guidelines for Autoimmune Pancreatitis, 2013 I. Concept and diagnosis of autoimmune pancreatitis. J Gastroenterol. 2014;49:567–88.PubMed

Ohara H, Okazaki K, Tsubouchi H, et al. Clinical diagnostic criteria of IgG4-related sclerosing cholangitis 2012. J Hepatobiliary Pancreat Sci. 2012;19:536–42.PubMed

Sah RP, Chari ST. Serologic issues in IgG4-related systemic disease and autoimmune pancreatitis. Curr Opin Rheumatol. 2011;23:108–13.PubMed

Zen Y, Fujii T, Harada K, et al. Th2 and regulatory immune reactions are increased in immunoglobin G4-related sclerosing pancreatitis and cholangitis. Hepatology. 2007;45:1538–46.PubMed

Miyake K, Moriyama M, Aizawa K, et al. Peripheral CD4+ T cells showing a Th2 phenotype in a patient with Mikulicz's disease associated with lymphadenopathy and pleural effusion. Mod Rheumatol. 2008;18:86–90.PubMed

Miyoshi H, Uchida K, Taniguchi T, et al. Circulating naive and CD4+CD25high regulatory T cells in patients with autoimmune pancreatitis. Pancreas. 2008;36:133–40.PubMed

Akitake R, Watanabe T, Zaima C, et al. Possible involvement of T helper type 2 responses to Toll-like receptor ligands in IgG4-related sclerosing disease. Gut. 2010;59:542–5.PubMed

Collison LW, Workman CJ, Kuo TT, et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature. 2007;450:566–9.PubMed

Devergne O, Hummel M, Koeppen H, et al. A novel interleukin-12 p40-related protein induced by latent Epstein-Barr virus infection in B lymphocytes. J Virol. 1996;70:1143–53.PubMedPubMedCentral

10.

Niedobitek G, Pazolt D, Teichmann M, et al. Frequent expression of the Epstein-Barr virus (EBV)-induced gene, EBI3, an IL-12 p40-related cytokine, in Hodgkin and Reed-Sternberg cells. J Pathol. 2002;198:310–6.PubMed

11.

Deshpande V, Zen Y, Chan JK, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol. 2012;25:1181–92.PubMed

12.

Miyara M, Yoshioka Y, Kitoh A, et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity. 2009;30:899–911.PubMed

13.

Liu W, Putnam AL, Xu-Yu Z, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med. 2006;203:1701–11.PubMedPubMedCentral

14.

Sallusto F, Mackay CR, Lanzavecchia A. The role of chemokine receptors in primary, effector, and memory immune responses. Annu Rev Immunol. 2000;18:593–620.PubMed

15.

Kanai K, Park AM, Yoshida H, et al. IL-35 suppresses lipopolysaccharide-induced airway eosinophilia in EBI3-deficient mice. J Immunol. 2017;198:119–27.PubMed

16.

Wirtz S, Billmeier U, McHedlidze T, et al. Interleukin-35 mediates mucosal immune responses that protect against T-cell-dependent colitis. Gastroenterology. 2011;141:1875–86.PubMedPubMedCentral

17.

Nakano S, Morimoto S, Suzuki S, et al. Immunoregulatory role of IL-35 in T cells of patients with rheumatoid arthritis. Rheumatology (Oxford). 2015;54:1498–506.

18.

Cai Z, Wong CK, Kam NW, et al. Aberrant expression of regulatory cytokine IL-35 in patients with systemic lupus erythematosus. Lupus. 2015;24:1257–66.PubMed

19.

Tomcik M, Zerr P, Palumbo-Zerr K, et al. Interleukin-35 is upregulated in systemic sclerosis and its serum levels are associated with early disease. Rheumatology (Oxford). 2015;54:2273–82.

20.

Wong CK, Leung TF, Chu IM, et al. Aberrant expression of regulatory cytokine IL-35 and pattern recognition receptor NOD2 in patients with allergic asthma. Inflammation. 2015;38:348–60.PubMed

21.

Huang CH, Loo EX, Kuo IC, et al. Airway inflammation and IgE production induced by dust mite allergen-specific memory/effector Th2 cell line can be effectively attenuated by IL-35. J Immunol. 2011;187:462–71.PubMed

22.

Liu JQ, Liu Z, Zhang X, et al. Increased Th17 and regulatory T cell responses in EBV-induced gene 3-deficient mice lead to marginally enhanced development of autoimmune encephalomyelitis. J Immunol. 2012;188:3099–106.PubMedPubMedCentral

23.

Collison LW, Chaturvedi V, Henderson AL, et al. IL-35-mediated induction of a potent regulatory T cell population. Nat Immunol. 2010;11:1093–101.PubMedPubMedCentral

24.

Sha X, Meng S, Li X, et al. Interleukin-35 inhibits endothelial cell activation by suppressing MAPK-AP-1 pathway. J Biol Chem. 2015;290:19307–18.PubMedPubMedCentral

25.

Dixon KO, van der Kooij SW, Vignali DA, et al. Human tolerogenic dendritic cells produce IL-35 in the absence of other IL-12 family members. Eur J Immunol. 2015;45:1736–47.PubMedPubMedCentral

26.

Wang RX, Yu CR, Dambuza IM, et al. Interleukin-35 induces regulatory B cells that suppress autoimmune disease. Nat Med. 2014;20:633–41.PubMedPubMedCentral

27.

Niedbala W, Wei XQ, Cai B, et al. IL-35 is a novel cytokine with therapeutic effects against collagen-induced arthritis through the expansion of regulatory T cells and suppression of Th17 cells. Eur J Immunol. 2007;37:3021–9.PubMed

28.

Batten M, Li J, Yi S, et al. Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells. Nat Immunol. 2006;7:929–36.PubMed

29.

Huber M, Steinwald V, Guralnik A, et al. IL-27 inhibits the development of regulatory T cells via STAT3. Int Immunol. 2008;20:223–34.PubMed

30.

Sheppard P, Kindsvogel W, Xu W, et al. IL-28, IL-29 and their class II cytokine receptor IL-28R. Nat Immunol. 2003;4:63–8.PubMed

31.

Kotenko SV, Gallagher G, Baurin VV, et al. IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. Nat Immunol. 2003;4:69–77.PubMed

32.

Commins S, Steinke JW, Borish L. The extended IL-10 superfamily: IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, and IL-29. J Allergy Clin Immunol. 2008;121:1108–11.PubMed

33.

Lauterbach H, Bathke B, Gilles S, et al. Mouse CD8alpha+ DCs and human BDCA3+ DCs are major producers of IFN-lambda in response to poly IC. J Exp Med. 2010;207:2703–17.PubMedPubMedCentral

34.

Li Y, Gao Q, Yuan X, et al. Adenovirus expressing IFN-lambda1 (IL-29) attenuates allergic airway inflammation and airway hyperreactivity in experimental asthma. Int Immunopharmacol. 2014;21:156–62.PubMed

35.

Srinivas S, Dai J, Eskdale J, et al. Interferon-lambda1 (interleukin-29) preferentially down-regulates interleukin-13 over other T helper type 2 cytokine responses in vitro. Immunology. 2008;125:492–502.PubMedPubMedCentral

36.

Yazdani Z, Rafiei A, Golpour M, et al. IL-35, a double-edged sword in cancer. J Cell Biochem. 2020;121:2064–76.PubMed

37.

Pelletier M, Maggi L, Micheletti A, et al. Evidence for a cross-talk between human neutrophils and Th17 cells. Blood. 2010;115:335–43.PubMed

38.

Canda-Sanchez A, Salgado FJ, Perez-Diaz A, et al. Differential distribution of both IL-12Rbeta chains in the plasma membrane of human T cells. J Membr Biol. 2009;227:1–12.PubMed

39.

Sumimoto K, Uchida K, Kusuda T, et al. The role of CD19+ CD24high CD38high and CD19+ CD24high CD27+ regulatory B cells in patients with type 1 autoimmune pancreatitis. Pancreatology. 2014;14:193–200.PubMed

40.

Shen P, Roch T, Lampropoulou V, et al. IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature. 2014;507:366–70.PubMedPubMedCentral

41.

Wojno ED, Hunter CA. New directions in the basic and translational biology of interleukin-27. Trends Immunol. 2012;33:91–7.PubMed

42.

Cox JH, Kljavin NM, Ramamoorthi N, et al. IL-27 promotes T cell-dependent colitis through multiple mechanisms. J Exp Med. 2011;208:115–23.PubMedPubMedCentral

43.

Tsuboi H, Matsuo N, Iizuka M, et al. Analysis of IgG4 class switch-related molecules in IgG4-related disease. Arthritis Res Ther. 2012;14:R171.PubMedPubMedCentral

Titel: Interleukin-35 promotes the differentiation of regulatory T cells and suppresses Th2 response in IgG4-related type 1 autoimmune pancreatitis
verfasst von: Takashi Ito
Toshihiro Tanaka
Koh Nakamaru
Takashi Tomiyama
Takashi Yamaguchi
Yugo Ando
Tsukasa Ikeura
Toshiro Fukui
Kazushige Uchida
Akiyoshi Nishio
Kazuichi Okazaki
Publikationsdatum: 06.05.2020
Verlag: Springer Singapore
Erschienen in: Journal of Gastroenterology / Ausgabe 8/2020
Print ISSN: 0944-1174
Elektronische ISSN: 1435-5922
DOI: https://doi.org/10.1007/s00535-020-01689-5

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