Interleukin‐33 overexpression is associated with liver fibrosis in mice and humans

Abstract

Interleukin-33 (IL-33), the most recently identified member of the IL-1 family, induces synthesis of T Helper 2 (Th2)-type cytokines via its heterodimeric ST2/IL-1RAcP receptor. Th2-type cytokines play an important role in fibrosis; thus, we investigated the role of IL-33 in liver fibrosis. IL-33, ST2 and IL-1RAcP gene expression was analysed in mouse and human normal (n= 6) and fibrotic livers (n= 28), and in human hepatocellular carcinoma (HCC; n= 22), using real-time PCR. IL-33 protein was detected in normal and fibrotic liver sections and in isolated liver cells using Western blotting and immunolocalization approaches. Our results showed that IL-33 and ST2 mRNA was overproduced in mouse and human fibrotic livers, but not in human HCC. IL-33 expression correlated with ST2 expression and also with collagen expression in fibrotic livers. The major sources of IL-33 in normal liver from both mice and human beings are the liver sinusoidal endothelial cells and, in fibrotic liver, the activated hepatic stellate cells (HSC). Moreover, IL-33 expression was increased in cultured HSC when stimulated by pro-inflammatory cytokines. In conclusion, IL-33 is strongly associated with fibrosis in chronic liver injury and activated HSC are a source of IL-33.

Interleukin-33 drives hepatic fibrosis through activation of hepatic stellate cells

“…of a representative study of three independent experiments are shown; comparisons between subgroups were performed by one-way ANOVA followed by a Newman-Keuls posttest: *Po0.05, **Po0.01, ***Po0.001 (compared with cells cultured in medium). 30 In our present work, we demonstrate that IL-33 is elevated in cirrhotic livers, and ILC2s are upregulated, along with hepatic fibrogenesis. 31 Furthermore, ST2-deficient mice reveal that IL-33/ST2 is both required and sufficient for BDL-induced liver inflammation and fibrosis.…”

“…30,33 Here, we demonstrate that hepatocytes are the primary sources of IL-33 in fibrotic liver. We assumed that on hepatocyte damage, released IL-33 might have a direct effect on HSCs, increasing secretion of both cytokines and collagen, as verified in vitro with cultured HSCs stimulated with rmIL-33.…”

Interleukin-33 Promotes Disease Progression in Patients with Primary Biliary Cirrhosis

“…Recently, an increasing body of literature has shown that IL-33 is related to the pathogenic mechanisms of fibrosis (Marvie et al 2010;Volarevic et al 2012;McHedlidze et al 2013). For example, IL-33 expression correlates with ST2 expression, and with collagen expression in fibrotic livers in mice and humans (Marvie et al 2010). IL-33-dependent innate lymphoid cells have also been reported to mediate hepatic fibrosis.…”

“…IL-33 is a cytokine involved in type 2 immunity and inflammatory responses, and has major effects on innate and adaptive cells, including innate lymphoid cell-2, T helper 2 cells, and alternatively activated M2 polarized macrophages. Recently, an increasing body of literature has shown that IL-33 is related to the pathogenic mechanisms of fibrosis (Marvie et al 2010;Volarevic et al 2012;McHedlidze et al 2013). For example, IL-33 expression correlates with ST2 expression, and with collagen expression in fibrotic livers in mice and humans (Marvie et al 2010).…”

“…The RNA was reverse-transcribed to complementary DNA using oligo (dT) primers at 42°C for 30 min and at 95°C for 5 min. Quantitation of the IL-33 mRNA was determined by staining with the fluorogenic dye SYBR Green as previously described (Marvie et al 2010). Each measurement was performed in duplicate.…”