IL-37 suppresses the sustained hepatic IFN-γ/TNF-α production and T cell-dependent liver injury

• Published in: International immunopharmacology 2019-04, Vol.69, p.184-193
• Main Authors: Feng, Xin-Xia, Chi, Gang, Wang, Han, Gao, Yuan, Chen, Qian, Ru, Ying-Xia, Luo, Zhen-Long, Yan, Wei, Li, Pei-Yuan, Liu, Mei, Feng, Zuo-Hua, Tian, De-An
• Format: Article
• Language: English
• Subjects: Apoptosis; Bile; Cell activation; Cirrhosis; Concanavalin A; Cytokine expression; Cytokines; Damage; Fibrosis; Hepatic fibrosis; Hepatitis; Hepatocytes; IL-1β; IL-37; Immune system; Inflammation; Injury prevention; Interleukin 1 receptor antagonist; Interleukin 1 receptors; Interleukin 10; Interleukin 12; Interleukin 13; Interleukin 4; Liver; Liver cirrhosis; Lymphocytes; Lymphocytes T; Macrophages; T cell-dependent liver injury; TLR4 protein; Toll-like receptors; Tumor necrosis factor-α; γ-Interferon
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2019.01.037

T cell-dependent liver injury is an important reason for the massive hepatic damage and cirrhosis. So far it is unclear whether the development of the disease could be efficiently suppressed by anti-inflammatory cytokine that modulates innate immune cells. Here we report that anti-inflammatory cytokine IL-37 could efficiently suppress the sustained hepatic expression of IFN-γ and TNF-α, two critical cytokines for inducing hepatocyte apoptosis and liver fibrosis in T cell-dependent liver injury. IL-37 could directly suppress IFN-γ/TLR4 ligand-induced M1 activation of macrophages, thus reducing the expression of pro-inflammatory cytokines TNF-α, IL-1β, and IL-12. Moreover, IL-37 attenuated Th1 response in vivo and increased the expression of Th2 cytokines IL-4 and IL-13, which in turn promoted M2 activation of macrophages in the liver. The increase of M2 activation not only further reduced TNF-α, IL-1β and IL-12 expression, but also increased IL-10 and IL-1Ra expression in macrophages, thus more efficiently suppressing the hepatic IFN-γ expression. By suppressing IFN-γ/TNF-α expression, IL-37 suppressed the up-regulation and activation of MLKL that drives hepatocellular necrosis in T cell-dependent liver damage. Accordingly, IL-37 efficiently reduced liver injury and hepatic inflammation after the repeated ConA challenge and the induction of autoimmune hepatitis, and also suppressed hepatic fibrosis resulting from the sustained liver damage. This study showed that the direct and indirect effect of IL-37 on macrophages could reduce the hepatic TNF-α expression, and also modulate IL-1β/IL-12 and IL-10/IL-1Ra expression to suppress the hepatic IFN-γ expression, thus suppressing the development of T cell-dependent liver injury such as autoimmune hepatitis. •IL-37 suppresses M1 activation of macrophages to reduce hepatic production of TNF-α.•IL-37 alters Th1/Th2 responses to increase M2 activation of hepatic macrophages.•IL-37 reduces IL-1β/IL-12 and increases IL-10/IL-1Ra to reduce IFN-γ in the liver.•IL-37 suppresses the up-regulation and activation of MLKL by reducing IFN-γ/TNF-α.•IL-37 efficiently suppresses the sustained liver injury and hepatic fibrosis.