Sex Hormones and HCV

An Unresolved Mystery

Radwa Y Mekky; Ahmed I Abdelaziz

Disclosures

Expert Rev Gastroenterol Hepatol. 2013;7(1):69-75. 

In This Article

Discrepancy in IFN Release Among Different Genders

Variation in IFN induction among males and females may help to explain the differences in immune response to HCV. Toll-like receptor (TLR) 7 is a receptor which recognizes HCV RNA. The activation of this receptor leads to IFN-α induction, which consequently activates interferon-stimulated genes (ISGs) that allow viral clearance (Figure 2).[27,28] TLR7 showed a higher sensitivity to TLR7 agonists in healthy females when compared with healthy males, which consequently led to enhanced production of IFN-α.[29]

Figure 2.

Impact of sex hormones on pre- and post-IFN release. (A) HCV attaches to cell surface receptors, and after uncoating the virus, binds to endosomal TLR7 which consequently leads to induction of IFN-α, -β, -λ and -γ via activation of several transcription factors. Among these transcription factors are IRF7 and NF-κB. Sex hormones regulate IFN release in several ways. For example, estrogen and progesterone were found to enhance expression of TLR7. However, progesterone was found to abrogate the expression of IRF7. Estrogen was also found to downregulate the expression of NF-κB. (B) After IFN is released they bind to their receptors, which activate the JAK/STAT pathway leading to production of ISGs. The JAK/STAT pathway is negatively regulated by certain transcription factors such as SOCs. Estrogen was found to attenuate the JAK/STAT pathway by enhancing the expression of SOCs and downregulating ISG expression.
+: increasing the expression; -: decreasing the expression; IFNAR: Interferon receptor; IRF7: Interferon regulatory factor 7; ISG: Interferon-stimulated gene; SOCS: Suppressors of cytokine release; TLR: Toll-like receptor.

Female sex hormones were reported to affect certain host factors that are important for IFN release. For example, estrogen was reported to suppress the maturation of dendritic cells, which are the main producers of IFN.[30] Estrogen was also found to negatively regulate NFκB, a transcription factor that is fundamental for production of IFN (Figure 2).[31] Progesterone was also reported to impair the antiviral immune response by decreasing the response of plasmacytoid dendritic cells through abrogating the activation of interferon regulatory factor 7, an important transcription factor for IFN production (Figure 2A).[32] However conflicting data by Meier et al. found a significant correlation between an increased production of IFN-α in healthy female plasmacytoid dendritic cells after being triggered with TLR7/8 ligands and plasma levels of progesterone (Figure 2A).[33]

The impact of testosterone on IFN release has received negligible attention in the literature. However, the discrepant rates of self-limited infection in males and females may be explained by the contrasting effects of estrogen and testosterone on the expression of the TLR family; where testosterone did not alter the expression of TLR on the surface of peripheral blood mononuclear cells (PBMCs) from healthy volunteers, while estrogen enhanced its expression (Figure 2A).[34]

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