Background & Aims Interleukin (IL)-17 signaling has been implicated in lung and skin fibrosis. We examined the role of IL-17 signaling in the pathogenesis of liver fibrosis in mice. Methods Using cholestatic and hepatotoxic models of liver injury, we compared the development of liver fibrosis in wild-type mice with that of IL-17RA^−/− mice and of bone marrow chimeric mice devoid of IL-17 signaling in immune and Kupffer cells (IL-17RA^−/− to wild-type and IL-17A^−/− to wild-type mice) or liver resident cells (wild-type to IL-17RA^−/− mice). Results In response to liver injury, levels of Il-17A and its receptor increased. IL-17A increased appeared to promote fibrosis by activating inflammatory and liver resident cells. IL-17 signaling facilitated production of IL-6, IL-1, and tumor necrosis factor-α by inflammatory cells and increased the expression of transforming growth factor-1, a fibrogenic cytokine. IL-17 directly induced production of collagen type I in hepatic stellate cells by activating the signal transducer and activator of transcription 3 (Stat3) signaling pathway. Mice devoid of Stat3 signaling in hepatic stellate cells (GFAPStat3^−/− mice) were less susceptible to fibrosis. Furthermore, deletion of IL-23 from immune cells attenuated liver fibrosis, whereas deletion of IL-22 exacerbated fibrosis. Administration of IL-22 and IL-17E (IL-25, a negative regulator of IL-23) protected mice from bile duct ligation-induced liver fibrosis. Conclusions IL-17 induces liver fibrosis through multiple mechanisms in mice. Reagents that block these pathways might be developed as therapeutics for patients with cirrhosis.

Chao Cui, Shuai Gao, Jingfei Shi, Kai Wang. Gut and Liver -0001;0:. https://doi.org/10.5009/gnl240539

To investigate the potential of promoter methylation of two tumor suppressor genes (TSGs) as biomarkers for hepatocellular carcinoma (HCC). A total of 189 subjects were included in this retrospective cohort, which contained 121 HCC patients without any history of curative treatment, 37 patients with chronic hepatitis B (CHB), and 31 normal controls (NCs). DNA samples were extracted from 400 μL of serum of each subject and then modified using bisulfite treatment. Methylation of the promoters of the TSGs (metallothionein 1M, MT1M; and metallothionein 1G, MT1G) was determined using methylation-specific polymerase chain reaction. The diagnostic value of combined MT1M and MT1G promoter methylation was evaluated using the area under the receiver operating characteristic curves. Our results indicated that the methylation status of serum MT1M (48.8%, 59/121) and MT1G (70.2%, 85/121) promoters in the HCC group was significantly higher than that in the CHB group (MT1M 5.4%, 2/37, P < 0.001; MT1G 16.2%, 6/37, P < 0.001) and NC group (MT1M 6.5%, 2/31, P < 0.001; MT1G 12.9%, 4/27, P < 0.001). Aberrant serum MT1M promoter methylation gave higher specificity to discriminate HCC from CHB (94.6%) and NCs (93.5%), whereas combined methylation of serum MT1M and MT1G promoters showed higher diagnostic sensitivity (90.9%), suggesting that they are potential markers for noninvasive detection of HCC. Furthermore, MT1M promoter methylation was positively correlated with tumor size (rs = 0.321, P < 0.001), and HCC patients with both MT1M and MT1G promoter methylation tended to show a higher incidence of vascular invasion or metastasis (P = 0.018). MT1M and MT1G promoter methylation may be used as serum biomarkers for noninvasive detection of HCC.

Background: G-protein-coupled bile acid receptor Gpbar1 (TGR5) is a newly identified liver tumor suppressor in carcinogenesis. This present study was therefore to determine the potential value of serum TGR5 promoter methylation in identifying hepatocellular carcinoma (HCC) from chronic hepatitis B (CHB) patients.