Abstract
Tumor necrosis factor (TNF)-α-stimulated protein 6 (TSG-6) is a secreted protein with diverse tissue protective and anti-inflammatory properties. We aimed to investigate its effects in treating mice with alcoholic hepatitis (AH) and the associated mechanisms. AH was induced in 8–10 week female C57BL/6N mice by chronic-binge ethanol feeding for 10 days. Intraperitoneal (i.p.) injection of recombinant mouse TSG-6 or saline were performed in mice on day 10. Blood samples and hepatic tissues were collected on day 11. Biochemistry, liver histology, flow cytometry, and cytokine measurements were conducted. Compared to the normal control mice, the AH mice had significantly increased liver/body weight ratio, serum alanine aminotransferase (ALT) and aspartate aminotransferases (AST), hepatic total cholesterol (TC), triglyceride (TG), malondialdehyde (MDA), hepatic macrophage infiltration, serum and hepatic interleukin (IL)-6, and tumor necrosis factor (TNF)-α, which were markedly reduced by i.p. injection of rmTSG-6. Compared to the normal control mice, the hepatic glutathione (GSH), accumulation of M2 macrophages, serum, and hepatic IL-10 and TSG-6 were prominently reduced in the AH mice, which were significantly enhanced after i.p. injection of rmTSG-6. Compared to the normal control mice, hepatic activation of signal transducer and activator of transcription 3 (STAT3) was significantly induced, which was markedly suppressed by rmTSG-6 treatment. TSG-6 was effective for the treatment of AH mice, which might be associated with its ability in inhibiting hepatic oxidative stress and inducing hepatic M2 macrophages polarization via suppressing STAT3 activation.
Highlights
Alcoholic liver disease (ALD) is a leading cause of mortality with increasing prevalence worldwide (Liangpunsakul et al, 2016)
We found that TSG-6 was effective in treating mice with alcoholic hepatitis (AH), alleviating the hepatic injury, steatosis, and oxidative stress
We showed that TSG-6 was able to inhibit the total number but induce the M2 type of macrophages infiltrating the livers of AH mice
Summary
Alcoholic liver disease (ALD) is a leading cause of mortality with increasing prevalence worldwide (Liangpunsakul et al, 2016). The spectrum of ALD is broad, ranging from alcoholic fatty liver, alcoholic steatohepatitis, alcoholic hepatitis (AH), fibrosis, cirrhosis, and hepatocellular carcinoma (Teschke, 2019). They may coexist in a given patient, and are often classified into three histological stages: alcoholic fatty liver or simple steatosis, AH, and alcoholic cirrhosis (MacSween and Burt, 1986). The recommended therapies for severe AH are corticosteroids or pentoxifylline if the patients had ongoing infections or acute renal failure (O'Shea et al, 2010a; O'Shea et al, 2010b; Mathurin et al, 2012). There is urgent need to explore other effective therapies
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