IFN-γ is reciprocally involved in the concurrent development of organ-specific autoimmunity in the liver and stomach

Abstract

Interferon (IFN)-γ acts as a critical proinflammatory mediator in autoimmune processes, whereas it exerts regulatory functions to limit tissue damage associated with inflammation. However, a detailed understanding of the complex roles of IFN-γ in the development of organ-specific autoimmunity is still lacking. Recently, we found that programmed cell death 1-deficient mice thymectomized 3 days after birth (NTx–PD-1^{− / −} mice) concurrently developed autoimmune hepatitis (AIH) and autoimmune gastritis (AIG). In this study, we investigated the roles of IFN-γ in the development of AIH and AIG in this mouse model. In NTx–PD-1^{− / −} mice, serum levels of IFN-γ were markedly elevated. Neutralization of IFN-γ prevented the development of AIG. However, the same treatment exacerbated hepatic T-cell infiltration in AIH. Because of the loss of anti-proliferative effects by IFN-γ, neutralization of IFN-γ increased T-cell proliferation in the spleen and liver, resulting in exacerbated T-cell infiltration in the liver. On the other hand, in the development of AIG, CD4⁺ T-cell migration into the gastric mucosa is essential for induction. CCL20 expression was up-regulated in the gastric mucosa, and anti-CCL20 suppressed CD4⁺ T-cell infiltration into the gastric mucosa. Importantly, anti-IFN-γ suppressed CCL20 expression and infiltration of CD4⁺ T cells in the gastric mucosa, whereas in vivo injection of recombinant IFN-γ up-regulated CCL20 expression in the stomach, suggesting that IFN-γ is critically involved in CD4⁺ T-cell accumulation in AIG by up-regulating local CCL20 expression. In conclusion, IFN-γ is involved differently in the development of AIH and of AIG. IFN-γ negatively regulates T-cell proliferation in fatal AIH, whereas it initiates development of AIG. These findings imply that increased production of IFN-γ induced by an organ-specific autoimmunity may trigger the concurrent development of another organ-specific autoimmune disease.

Keywords::

• IFN-γ
• proinflammatory mediator
• autoimmune gastritis
• CCL20
• regulatory function
• autoimmune hepatitis

Acknowledgements

We thank Dr Dovie Wylie for his assistance in preparation of the manuscript; Ms Chigusa Tanaka for her excellent technical assistance; and Drs Tasuku Honjo, Shuh Narumiya, Nagahiro Minato, Shimon Sakaguchi, Takeshi Watanabe, and Ichiro Aramori for their critical discussions and suggestions. Center for Innovation in Immunoregulative Technology and Therapeutics is supported in part by the Special Coordination Funds for Promoting Science and Technology of the Japanese Government and in part by Astellas Pharma, Inc., in the Formation of Innovation Center for Fusion of Advanced Technologies Program. This work is partially supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and a Grant-in-Aid for Research from The Kato Memorial Trust for Nambyo Research and The Waksman Foundation of Japan.

Declaration of Interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.