Testosterone Suppresses Hepatic Inflammation by the Downregulation of IL-17, CXCL-9, and CXCL-10 in a Mouse Model of Experimental Acute Cholangitis

Abstract

Autoimmune liver diseases predominantly affect women. In this study, we aimed to elucidate how sex affects autoimmune hepatic inflammation. Acute experimental cholangitis was induced by adoptive transfer of OVA-specific CD8+ T cells into mice, which express the cognate Ag on cholangiocytes. In contrast to previous mouse models of cholangitis, this model displayed a strong sexual dimorphism: female mice developed marked cholangitis, whereas male mice were resistant to cholangitis induction. The recruitment of endogenous CD4+ T cells, but not transferred CD8+ T cells into female livers was strongly increased. These cells expressed higher amounts of the proinflammatory cytokine IL-17, which was at least in part responsible for the liver inflammation observed. The recruitment of endogenous CD4+ T cells was associated with increased expression of the chemokines CXCL-9 and CXCL-10 in female livers. The sex-specific factor responsible for the observed differences was found to be testosterone: male mice could be rendered susceptible to liver inflammation by castration, and testosterone treatment was sufficient to completely suppress liver inflammation in female mice. Accordingly, testosterone treatment of female mice significantly reduced the expression of IL-17A, CXCL-9, and CXCL-10 within the liver. Serum testosterone levels of untreated mice negatively correlated with the IL-17, CXCL-9, and CXCL-10 expression in the liver, further supporting a role for testosterone in hepatic immune homeostasis. In conclusion, testosterone was found to be the major determinant of the observed sexual dimorphism. Further study into the role of testosterone for liver inflammation could lead to novel treatment targets in human autoimmune liver diseases.

Immunology of hepatic diseases during pregnancy

“…Recently, it has been described that testosterone has immunosuppressive properties in mice with experimental cholangitis and is able to completely protect female mice from antigen induced cholangitis [212].…”

Obesity and sex interact in the regulation of Alzheimer's disease

“…Moreover, low testosterone levels were shown to correlate with increased mortality, independent of metabolic syndrome, diabetes, or cardiovascular disease, but dependent on levels of the inflammatory enzymes, IL-6 and CRP (Laughlin et al, 2008), pointing to the interplay between androgens and inflammation. Experimental evidence suggests that androgens can reduce indices of inflammation (Norata et al, 2006; Schwinge et al, 2015). There is some evidence that testosterone treatment in aging men can lower inflammatory markers such as CRP (Giltay et al, 2008; Kalinchenko et al, 2010), though efficacy remains to be firmly established.…”

Free testosterone concentration is inversely associated with markers of liver fibrosis in men with type 2 diabetes mellitus

“…This may help clinicians to prevent future cases of cirrhosis and hepatocellular carcinoma. mice susceptible to liver inflammation [31]. Moreover, the serum testosterone levels of male and female mice correlated negatively with IL-17, CXCL-9, and CXCL-10 expression in the liver, which was at least partly responsible for the liver inflammation observed.…”

“…Moreover, the serum testosterone levels of male and female mice correlated negatively with IL-17, CXCL-9, and CXCL-10 expression in the liver, which was at least partly responsible for the liver inflammation observed. On the other hand, testosterone treatment was sufficient to completely suppress liver inflammation in female mice [31]. Additionally, testosterone treatment of female mice significantly reduced the expression of IL-17A, CXCL-9, and CXCL-10 within the liver.…”