Purpose We sought to determine the role IL-33 and its receptor ST2, a novel alarmin signaling in the IL-1 family, by which contributes to inflammatory and innate immune response following liver ischemia reperfusion (I/R) injury.

Methods Wild type (WT), IL-33-, and ST2-KO mice were subjected to a partial (70%) warm hepatic I/R model. Recombinant IL-33 (rIL-33) was administered in select groups and liver damage was assessed using liver enzyme. Hepatocytes (HCs) and liver sinusoidal endothelial cells (LSECs) were isolated and exposed to hypoxia or H₂O₂. Protein expressions of IL-33, ST2, and MAP kinases were determined by Western blot. The cytokine levels were assessed using real-time PCR or ELISA. Infiltration of innate immune cells such as natural killer (NK) cells, neutrophils, and inflammatory monocytes following liver I/R was evaluated by flow cytometry.

Results Liver tissue level of IL-33 and ST2 were elevated after I/R injury compared with sham operation. Both IL-33- and ST2-KO mice conferred significant protection compared to controls suggesting a pro-inflammatory role of IL-33/ST2 signaling in liver I/R.

However, rIL-33 treatment led to significantly increased ALT levels compared to controls after liver I/R. Activation of MAP kinases as well as NF-ΚB was observed significantly less in IL-33-KO mice compared with WT mice after liver I/R. Both hypoxia and H₂O₂ treatment led to the release of IL-33 from LSECs with a time- or dose-dependent manner. Interestingly, ST2 were constitutively expressed on HCs and increased in response to hypoxic stress. In addition, rIL-33 treatment increased activation of MAP kinases in HCs. Significant increase of NK cells, neutrophils and inflammatory monocytes were observed in WT mice after liver I/R whereas the ablation of IL-33 conferred stable cell numbers of innate immune cells compared with sham mice.

Conclusion Oxidative stress induces release of IL-33 from LSECs and that IL-33/ST2 contributes to inflammation and organ damage after liver I/R injury. Furthermore, ST2 signaling in HCs provides evidence that parenchymal cells, together with immune cells, may play an important role in responding to IL-33.

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