Interleukin-37 exacerbates liver inflammation and promotes IFN-γ production in NK cells

Interleukin (IL)-37, a unique member of the IL-1 family, is known for its anti-inflammatory properties. However, its effects on immune-mediated liver diseases, such as primary biliary cholangitis (PBC) and acute immune-mediated hepatitis, remain unclear. Using mouse models of autoimmune cholangitis and hepatitis induced by 2-OA-OVA and concanavalin A (Con A) respectively, we introduced the human IL-37 gene via a liver-preferred adeno-associated virus vector (AAV-IL-37) to mice, as mice lack endogenous IL-37. Our findings reveal that IL-37 did not affect autoimmune cholangitis. Surprisingly, IL-37 exacerbated inflammation in Con A-induced hepatitis rather than mitigating it. Mechanistic insights suggest that this exacerbation involves the interferon (IFN)-gamma pathway, supported by elevated serum IFN-gamma levels in AAV-IL-37-treated Con A mice. Specifically, IL-37 heightened the number of hepatic NK and NKT cells, increased the production of the NK cell chemoattractant CCL5, and elevated the frequency of hepatic NK and NKT cells expressing IFN-gamma. Moreover, IL-37 enhanced IFN-gamma secretion from NK cells when combined with other proinflammatory cytokines, highlighting its synergistic effect in promoting IFN-gamma production. These unexpected outcomes underscore a novel role for IL-37 in exacerbating liver inflammation during immune-mediated liver diseases, implicating its influence on NK cells and the production of IFN-gamma by these cells.