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

Interferon (IFN)-gamma 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-gamma 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-gamma in the development of AIH and AIG in this mouse model. In NTx-PD-1(-/-) mice, serum levels of IFN-gamma were markedly elevated. Neutralization of IFN-gamma 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-gamma , neutralization of IFN-gamma 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-gamma suppressed CCL20 expression and infiltration of CD4(+) T cells in the gastric mucosa, whereas in vivo injection of recombinant IFN-gamma up-regulated CCL20 expression in the stomach, suggesting that IFN-gamma is critically involved in CD4(+) T-cell accumulation in AIG by up-regulating local CCL20 expression. In conclusion, IFN-gamma is involved differently in the development of AIH and of AIG. IFN-gamma negatively regulates T-cell proliferation in fatal AIH, whereas it initiates development of AIG. These findings imply that increased production of IFN-gamma induced by an organ-specific autoimmunity may trigger the concurrent development of another organ-specific autoimmune disease.