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

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

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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Abbreviations

IgG4-RD:

IgG4-related disease

AIP:

Autoimmune pancreatitis

TGF-β:

Transforming growth factor-β

Tregs:

Regulatory T cells

nTregs:

Naïve regulatory T cells

Bregs:

Regulatory B cells

EBI3:

Epstein–Barr virus induced 3

ICDC:

International Consensus Diagnostic Criteria

IAP:

International Association of Pancreatology

ACP:

Alcoholic chronic pancreatitis

HC:

Healthy control

PBMC:

Peripheral blood mononuclear cells

eTregs:

Effector regulatory T cells

Foxp3:

Forkhead box P3

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

DCs:

Dendritic cells

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Acknowledgements

This study was partially supported by (1) Grant-in-Aid for Scientific Research (C) of the Ministry of Culture and Science of Japan (20590810, 23591017, 24591020, 12008507, 17877850, 17K09468, 15K09052, 19K17476), (2) the Research Program on Intractable Diseases, from the Ministry of Labor and Welfare of Japan, and (3) grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan, (4) the Research Program from the Japan Medical Research and Development (AMED) (17824893), (5) The branding program as a world-leading research university on intractable immune and allergic diseases supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan, and (6) the Research grant from Kansai Medical University.

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Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, The Third Department of Internal Medicine, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan

    Takashi Ito, Toshihiro Tanaka, Koh Nakamaru, Takashi Tomiyama, Takashi Yamaguchi, Yugo Ando, Tsukasa Ikeura, Toshiro Fukui, Akiyoshi Nishio & Kazuichi Okazaki

  2. Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi University, 185-1 Kohasu Okocho, Nankoku, Kochi, 783-8505, Japan

    Kazushige Uchida

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  1. Takashi Ito
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by TI and TT. The first draft of the manuscript was written by TI and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Kazuichi Okazaki.

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535_2020_1689_MOESM1_ESM.pdf

Supplementary file1 Supplementary Fig. 1 a There was no significant difference between type 1 AIP and ACP in IL-28 level. There was significant difference between type 1 AIP and HC in IL-28 level. b. There was no significant correlation between IL-28 and IgG4 in patients with type 1 AIP. AIP autoimmune pancreatitis, ACP alcoholic chronic pancreatitis, HC healthy control. Supplementary Fig. 2 Correlation between IL-35 and T-Bil, p-Amy, AST, ALT, WBC, Hb, Plt, CRP, ALP, HbA1c and BT-PABA test in patients with type 1 AIP. There were no significant correlations between IL-35 and all serum data. T-Bil total bilirubin, p-amy pancreatic amylase, AST aspartate transaminase, ALT alanine transaminase, WBC white blood cell, Hb hemoglobin, Plt platelet, CRP C-reactive protein, ALP alkaline phosphatase, HbA1c hemoglobin A1c, BT-PABA N-benzoyl–L–tyrosyl–p-aminobenzoic acid, AIP autoimmune pancreatitis. (PDF 106 kb)

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Ito, T., Tanaka, T., Nakamaru, K. et al. Interleukin-35 promotes the differentiation of regulatory T cells and suppresses Th2 response in IgG4-related type 1 autoimmune pancreatitis. J Gastroenterol 55, 789–799 (2020). https://doi.org/10.1007/s00535-020-01689-5

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