17β-Estradiol enhances the activation of IFN-α signaling in B cells by down-regulating the expression of let-7e-5p, miR-98-5p and miR-145a-5p that target IKKε

The activation of IFN-α signaling in B cells contributes to the pathogenesis of systemic lupus erythematosus (SLE). Many studies suggest that estrogens are closely related to the gender difference in the prevalence of SLE. However, the underlying mechanism of the interaction between estrogens and the activation of IFN-α signaling in SLE B cells remains incompletely understood. In the present study, we first found that healthy female mice showed an up-regulated type I IFN-induced gene signature in B cells compared with age-matched male mice, and an in vivo study revealed that the gender difference was related to 17β-estradiol. Moreover, we found that 17β-estradiol could enhance the activation of IFN-α signaling in an ERα-dependent manner by down-regulating the expression of three microRNAs, including let-7e-5p, miR-98-5p and miR-145a-5p. These microRNAs could target the 3′UTR of the IKKε-encoding gene IKBKE directly and regulate the expression of IKKε, which can promote the activation of IFN-α signaling. In addition, compared with age-matched male mice, female mice showed a higher level of IKKε and lower levels of let-7e-5p, miR-98-5p and miR-145a-5p in B cells. Moreover, peripheral blood mononuclear cells from women showed a higher level of IKKε and lower levels of let-7e-5p, miR-98-5p and miR-145a-5p compared with those from age-matched men. These data suggest that 17β-estradiol amplifies the activation of IFN-α signaling in B cells via IKKε by down-regulating the expression of let-7e-5p, miR-98-5p and miR-145a-5p. Our findings may provide a new perspective for understanding the mechanism underlying the gender difference in the prevalence of SLE.