Estrogen upregulates proinflammatory IFNγ via IL‐12, IL‐27, and STAT4β phosphorylation

Abstract

Estrogen has been shown to be involved in many autoimmune diseases. Estrogen-modulated induction of IFNγ and IFNγ-inducible molecules are of key importance due to their potential role in autoimmunity. Therefore, we investigated IFNγ-inducing cytokines and related molecular pathways in splenocytes from estrogen-treated mice. A key IFNγ-inducing cytokine, IL-12p70, was increased in estrogen-treated mice compared to controls. Exposure of splenocytes from estrogen-treated mice to Con-A or rIL-12 induced selective phosphorylation of STAT4β with corresponding increase in expression of IFNγ, IFNγ-inducible nitric oxide, IL6, MCP1. This increase was followed by decreased expression of Th2 transcription factors (STAT6 and STAT5) in estrogen-treated mice. The modulation of IL-12-inducible molecules by estrogen could be due to a macrophage-derived Th1 early-inducing cytokine IL-27. Estrogen-treated mice had noticeably increased IL-27p28 in both from Con-A and LPS stimulated splenocytes and macrophages. rIL-27 also increased T-bet from estrogen samples. Splenocytes from estrogen-treated mice pretreated with IL-27 and then cultured with rIL-12 showed an increasing trend in IFNγ. These findings provide fresh insight into the potential role of estrogen in regulating IFNγ-inducing cytokines and may lead to novel therapeutic approaches in treating autoimmune diseases.