IL-33-ST2 Axis in Liver Disease: Progression and Challenge
Table 1
Studies on the roles of IL-33 and ST2 in liver diseases.
Disease
Result
Ref
Fatty liver disease
(i) The mRNA and protein levels of both IL-33 and ST2 were increased in the mouse model of HFD-induced hepatic steatosis, and treatment with IL-33 alleviated hepatic steatosis. (ii) ST2−/− mice fed with HFD exhibited increased weight gain, severe hepatic steatosis, and inflammation. (iii) The IL-33 mRNA levels in serum and liver were increased in NAFLD patients.
(i) Serum IL-33 levels in CHC patients were significantly higher than those in HCs while decreased after treatment with interferon and were correlated with the ALT and AST concentrations. (ii) Serum IL-33 concentrations in CHC patients were positively correlated with the levels of serum HCV RNA. (iii) CHB patients with high serum ALT concentrations showed higher serum IL-33 and ST2 levels. (iv) In poly(I:C)-induced murine fulminant hepatitis, the expression of IL-33 was upregulated, and in NK-depleted poly(I:C)-treated mice, liver injury was severe while NKT-deficient mice showed hepatoprotection against poly(I:C)-induced hepatitis accompanied by an increased number of IL-33-expressing hepatocytes. (v) IL-33-knockout mice infected by LCMV produced fewer IFN-γ+ γδ T and NK cells, and rIL-33 treatment facilitated IFN-γ-producing γδ T and NK cells and inhibited IL-17+ γδ T cells. (vi) IL-33 and ST2 levels were increased in mouse liver after Ad infection. Injection of rIL-33 resulted in a decrease in serum ALT levels and the number of Councilman bodies in the liver; meanwhile, Treg cells were upregulated and TNF-α levels in the liver decreased. (vii) ST2-deficient mice developed severer hepatitis induced by Con A with a higher number of mononuclear cells and higher level of proinflammatory cytokines in the liver. IL-33 also suppressed caspase-3 activation and BAX expression as well as enhanced Bcl-2 expression in the liver. (viii) NKT-deficient mice performed resistant to Con A-induced hepatitis and lacked IL-33 expression in liver cells. (ix) IL-33 expression in hepatocytes was blocked during Con A-induced acute hepatitis in TRAIL-deficient mice. (x) The severity of liver injury in IL-33−/− mice was positively correlated with the levels of TNF-α and IL-1β and the number of NK cells infiltrating into the liver. (xi) rIL-33 exacerbated Con A-induced hepatitis, while pretreatment of an IL-33-blocking antibody exhibited a protective effect.
(i) In mouse and human fibrotic livers, IL-33 and ST2 mRNA was overexpressed and the major sources of IL-33 were HSCs. (ii) IL-33 led to activation and accumulation of ILC2 through ST2 signalling in the liver, and activated ILC2 produced IL-13; then, IL-13 initiated activation and differentiation of HSCs. (iii) In ST2-deficient mice with liver fibrosis, the activation of HSCs was decreased and in vitro HSCs activated by rIL-33 release IL-6, TGF-β, α-SMA, and collagen. (iv) Serum IL-33 levels of PBC patients were positively correlated with the severity of PBC.
(i) A high level of IL-33 mainly produced by CD8+ CD62L− KLRG1+ CD107a+ T cells might indicate prolonged patient survival. (ii) A high level of serum sST2 is regarded as a negative HCC prognostic factor. (iii) IL-33 presented a significant protective effect on liver ischemia/reperfusion mouse model with attenuated liver damage and limited inflammatory activity. (iv) IL-33 participated in hepatic granuloma pathology during Schistosoma japonicum infection. (v) In Leishmania donovani-infected liver mice, the IL-33/ST2 axis suppressed Th1 response and patients with visceral leishmaniasis showed higher serum IL-33 levels.
