DHEA and Its Metabolites Reduce the Cytokines Involved in the Inflammatory Response and Fibrosis in Primary Biliary Cholangitis

Dehydroepiandrosterone (DHEA) is an abundant steroid and precursor of sex hormones. During aging, the reduction in DHEA synthesis causes a significant depletion of estrogens and androgens in different organs, such as the ovaries, brain, and liver. Primary Biliary Cholangitis (PBC) is a cholestatic liver disease that begins with immune-mediated bile duct damage, and is followed by liver fibrosis, and finally, cirrhosis. PBC primarily affects postmenopausal women, with an average age of diagnosis of 65 years, but younger women are also affected. Here, we analyzed the levels of DHEA, estradiol (E2), and estriol (E3) in the PBC sera of females at an age of diagnosis under 40 (n = 37) and above 65 (n = 29). Our results indicate that in PBC patients at an age of diagnosis under 40, E2 was significantly lower compared to that in healthy women. In contrast, the levels of DHEA and E3 were in a normal range. Furthermore, ELISA assays revealed that in PBC patients at an age of diagnosis above 65, the levels of DHEA, E2, and E3 significantly declined in comparison to those in younger patients. In addition, flow cytometry analysis showed that the level of IL-8 significantly decreased while the level of TNF-alpha increased in older PBC patients compared to younger ones. Moreover, we showed for the first time that the sulfonated form of DHEA, DHEA-S, reduces the levels of both pro-inflammatory interleukins, IL-8 and TNF-alpha, in PBC-like cholangiocytes (H69-miR506), while it diminishes the level of the pro-fibrotic interleukin, IL-13, in hepatocytes (Hep-G2). Finally, we demonstrated that the expression of the pro-fibrotic agent TGF-beta significantly increased in both the early (F0-F3) and cirrhotic (F4) stages of PBC, and this elevation was accompanied by higher alpha-SMA expression.

Automated summary

Dehydroepiandrosterone (DHEA) is a steroid precursor that decreases with aging, leading to reduced levels of sex hormones. Primary Biliary Cholangitis (PBC) is a liver disease characterized by bile duct damage and fibrosis. In PBC patients, younger individuals have lower levels of estradiol (E2), while older patients have decreased levels of DHEA, E2, and estriol (E3). Older PBC patients also show reduced IL-8 levels and increased TNF-alpha levels. Additionally, the sulfonated form of DHEA, DHEA-S, reduces pro-inflammatory interleukins in PBC-like cholangiocytes and diminishes the pro-fibrotic interleukin IL-13 in hepatocytes. TGF-beta expression is elevated in both early and cirrhotic stages of PBC, accompanied by higher alpha-SMA expression.