IL-22 inactivates hepatic stellate cells via downregulation of the TGF-ß1/Notch signaling pathway.

ABSTRACT

Interleukin-22 (IL-22) inhibits liver fibrosis by inducing hepatic stellate cell (HSC) senescence, primarily through the activation of signal transducer and activator of transcription 3 signaling. However, whether other signaling pathways are involved remains unknown. The present study assessed the regulatory mechanism between IL­22 and the Notch signaling pathway in vitro. The results revealed that IL­22 had anti­proliferative effects on HSC­T6 cells, and cellular inactivation was reflected by simultaneous inhibition of α­smooth muscle actin, transforming growth factor-ß1 (TGF­ß1), tumor necrosis factor-α and intercellular adhesion molecule 1. Treatment with TGF­ß1 resulted in significant Notch3 upregulation and activation of its downstream effectors Hes family basic helix­loop­helix (bHLH) transcription factor (Hes)-1, Hes­5 and Hes related family BHLH transcription factor with YRPW motif 1. Furthermore, this effect was markedly reversed by further treatment with IL­22, indicating there may be regulatory cascades of IL­22/TGF­ß1/Notch signaling in HSC­T6 cells. The results of the present study demonstrated an inhibitory function of IL­22 towards Notch signaling in hepatic cells, providing evidence that Notch may serve as a novel target for liver fibrosis.