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 (IL-33) has now emerged as a cytokine with diverse and pleiotropic functions in various infectious and inflammatory diseases. IL-33 is expressed by epithelial cells, endothelial cells, fibroblasts, and hepatocytes. The target cells of IL-33 are Th2 cells, basophils, dendritic cells, mast cells, macrophages, NKT cells, and nuocytes, newly discovered natural helper cells/innate lymphoid cells bearing the ST2 receptor. IL-33 has dual functions, both as a traditional cytokine and as a nuclear factor that regulates gene transcription. IL-33 functions as an “alarmin” released following cell death, as a biomarker, and as a vaccine adjuvant, with proinflammatory and protective effects during various infections. The exacerbated or protective role of the IL-33/ST2 axis during different infections is dependent upon the organ involved, type of infectious agent, whether the infection is acute or chronic, the invasiveness of the infectious agent, the host immune compartment, and cellular and cytokine microenvironments. In this review, we focus on recent advances in the understanding of the role of the IL-33/ST2 axis in various viral, bacterial, fungal, helminth, and protozoal infectious diseases gained from animal models and studies in human patients. The functional role of IL-33 and ST2 during experimentally induced infections has been summarized by accumulating the data for IL-33- and ST2-deficient mice or for mice exogenously administered IL-33. In summary, exploring the crucial and diverse roles of the IL-33/ST2 axis during infections may help in the development of therapeutic interventions for a wide range of infectious diseases.

Interleukin (IL)-33, a member of the IL-1 cytokine family, positively correlates with acute hepatitis and chronic liver failure in mice and humans. IL-33 is expressed in hepatocytes and is regulated by natural killer T (NKT) cells during concanavalin A (ConA)-induced acute liver injury. Here, we investigated the molecular mechanisms underlying the expression of IL-33 during acute hepatitis. The expression of IL-33 and its regulation by death receptor pathways was investigated after the induction of ConA-acute hepatitis in wildtype (WT), perforin^−/−, tumor necrosis factor related apoptosis inducing ligand (TRAIL)^−/−, and NKT cell-deficient (CD1d^−/−) mice. In addition, we used a model of acute liver injury by administering Jo2/Fas-antibody or D-galactosamine-tumor necrosis factor alpha (TNFα) in WT mice. Finally, the effect of TRAIL on IL-33 expression was assessed in primary cultured murine hepatocytes. We show that IL-33 expression in hepatocytes is partially controlled by perforin during acute liver injury, but not by TNFα or Fas ligand (FasL). Interestingly, the expression of IL-33 in hepatocytes is blocked during ConA-acute hepatitis in TRAIL-deficient mice compared to WT mice. In contrast, administration of recombinant murine TRAIL associated with ConA-priming in CD1d-deficient mice or in vitro stimulation of murine hepatocytes by TRAIL but not by TNFα or Jo2 induced IL-33 expression in hepatocytes. The IL-33-deficient mice exhibited more severe ConA liver injury than WT controls, suggesting a protective effect of IL-33 in ConA-hepatitis. Conclusion: The expression of IL-33 during acute hepatitis is dependent on TRAIL, but not on FasL or TNFα. (HEPATOLOGY 2012)

Interleukin‐33 (IL‐33) is thought to be released during cellular death as an alarmin cytokine during the acute phase of disease, but its regulation in vivo is poorly understood. We investigated the expression of IL‐33 in two mouse models of acute hepatitis by administering either carbon tetrachloride (CCl₄) or concanavalin A (ConA). IL‐33 was overexpressed in both models but with a stronger induction in ConA‐induced hepatitis. IL‐33 was weakly expressed in vascular and sinusoidal endothelial cells from normal liver and was clearly induced in CCl₄‐treated mice. Surprisingly, we found that hepatocytes strongly expressed IL‐33 exclusively in the ConA model. CD1d knock‐out mice, which are deficient in NKT cells and resistant to ConA‐induced hepatitis, no longer expressed IL‐33 in hepatocytes following ConA administration. Interestingly, invariant NKT (iNKT) cells adoptively transferred into ConA‐treated CD1d KO mouse restored IL‐33 expression in hepatocytes. This strongly suggests that NKT cells are responsible for the induction of IL‐33 in hepatocytes.