Mutually positive regulatory feedback loop between interferons and estrogen receptor-alpha in mice: implications for sex bias in autoimmunity.

Abstract

Systemic lupus erythematosus (SLE), an autoimmune disease, predominantly affects women of childbearing age. Moreover, increased serum levels of interferon-alpha (IFN-alpha) are associated with the disease. Although, the female sex hormone estrogen (E2) is implicated in sex bias in SLE through up-regulation of IFN-gamma expression, the molecular mechanisms remain unknown. Here we report that activation of IFN (alpha or gamma)-signaling in immune cells up-regulates expression of estrogen receptor-alpha (ERalpha; encoded by the Esr1 gene) and stimulates expression of target genes.We found that treatment of mouse splenic cells and mouse cell lines with IFN (alpha or gamma) increased steady-state levels of ERalpha mRNA and protein. The increase in the ERalpha mRNA levels was primarily due to the transcriptional mechanisms and it was dependent upon the activation of signal transducer and activator of transcription-1 (STAT1) factor by IFN. Moreover, the IFN-treatment of cells also stimulated transcription of a reporter gene, expression of which was driven by the promoter region of the murine Esr1 gene. Notably, splenic cells from pre-autoimmune lupus-prone (NZB x NZW)F(1) female mice had relatively higher steady-state levels of mRNAs encoded by the IFN and ERalpha-responsive genes as compared to the age-matched males.Our observations identify a novel mutually positive regulatory feedback loop between IFNs and ERalpha in immune cells in mice and support the idea that activation of this regulatory loop contributes to sex bias in SLE.