ABSTRACT
AIMS: Interleukin (IL)-22 activates multiple signaling pathways to exert anti-inflammatory effects, but few studies have examined whether and how IL-22 may shift macrophage polarization between M1 (pro-inflammatory) and M2 (anti-inflammatory) states and thereby influence the progression of hepatic fibrosis. MAIN METHODS: Utilized CCl4 to induce liver fibrosis in mice, detected the role of IL-22 in inhibiting liver fibrosis by regulating Kupffer cells (KCs) polarization in vivo and in vitro. U937 cells were used to confirm the mechanism of IL-22 regulating macrophage polarization via the STAT3/Erk/Akt pathways. Human liver specimens were collected to verify the correlation between the levels of IL-22 and KCs during liver fibrogenesis. KEY FINDINGS: During CCl4-induced liver fibrosis progression in mice, adding exogenous IL-22 significantly inhibited pro-fibrogenic and macrophage phenotype-altering factors secreted by M1-KCs, and it increased the number of M2-KCs. In co-cultures of hepatic stellate cells and KCs from mice treated with IL-22, a high M2/M1-KCs ratio inhibited collagen production and stellate cell activation. These results suggest that IL-22 can increase the ratio of M2-KCs to M1-KCs and thereby attenuate the progression of liver fibrosis. Mechanistic studies in vitro showed that IL-22 promoted polarization of lipopolysaccharide-treated U937 macrophages from M1 to M2. The cytokine exerted these effects by activating the STAT3 pathway while suppressing Erk1/2 and Akt pathways. Furthermore, immunofluorescent staining in human liver specimens confirmed that IL-22 levels positively correlated with the number of M2-KCs during liver fibrogenesis. SIGNIFICANCE: IL-22 regulates the STAT3/Erk/Akt to increase the M2/M1-KCs ratio and thereby slow liver fibrogenesis.
Subject(s)
Interleukins/pharmacology , Kupffer Cells/metabolism , Liver Cirrhosis/metabolism , MAP Kinase Signaling System/physiology , Proto-Oncogene Proteins c-akt/metabolism , STAT3 Transcription Factor/metabolism , Animals , Cell Polarity/drug effects , Cell Polarity/physiology , Coculture Techniques , Hepatic Stellate Cells/drug effects , Hepatic Stellate Cells/metabolism , Hepatic Stellate Cells/pathology , Humans , Interleukins/therapeutic use , Kupffer Cells/drug effects , Liver Cirrhosis/drug therapy , Liver Cirrhosis/pathology , MAP Kinase Signaling System/drug effects , Mice , Mice, Inbred C57BL , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , U937 Cells , Interleukin-22ABSTRACT
Liver fibrosis is the common pathological basis of all chronic liver diseases, and is the necessary stage for the progression of chronic liver disease to cirrhosis. As one of pathogenic factors, inflammation plays a predominant role in liver fibrosis via communication and interaction between inflammatory cells, cytokines, and the related signaling pathways. Damaged hepatocytes induce an increase in pro-inflammatory factors, thereby inducing the development of inflammation. In addition, it has been reported that inflammatory response related signaling pathway is the main signal transduction pathway for the development of liver fibrosis. The crosstalk regulatory network leads to hepatic stellate cell activation and proinflammatory cytokine production, which in turn initiate the fibrotic response. Compared with the past, the research on the pathogenesis of liver fibrosis has been greatly developed. However, the liver fibrosis mechanism is complex and many pathways involved need to be further studied. This review mainly focuses on the crosstalk regulatory network among inflammatory cells, cytokines, and the related signaling pathways in the pathogenesis of chronic inflammatory liver diseases. Moreover, we also summarize the recent studies on the mechanisms underlying liver fibrosis and clinical efforts on the targeted therapies against the fibrotic response.
