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(The FASEB Journal. 2008;22:lb428)
© 2008 FASEB
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lb428

Estrogen upregulates proinflammatory IFN{gamma} via IL-12, IL-27, and STAT4β phosphorylation

Ebru Karpuzoglu1,2, Rebecca A Phillips1, Rujuan Dai1, Robert M Gogal, Jr1, Deena Khan1 and S. Ansar Ahmed1

1 Department of Biomedical Sciences & Pathobiology, Virginia Tech, Blacksburg, VA,
2 Institute of Gene and Transplantation, Baskent University, Ankara, Turkey

ABSTRACT

Estrogen has been shown to be involved in many autoimmune diseases. Estrogen-modulated induction of IFN{gamma} and IFN{gamma}-inducible molecules are of key importance due to their potential role in autoimmunity. Therefore, we investigated IFN{gamma}-inducing cytokines and related molecular pathways in splenocytes from estrogen-treated mice. A key IFN{gamma}-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 IFN{gamma}, IFN{gamma}-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 IFN{gamma}. These findings provide fresh insight into the potential role of estrogen in regulating IFN{gamma}-inducing cytokines and may lead to novel therapeutic approaches in treating autoimmune diseases.





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