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Estrogen Up-Regulates Hepatic Expression of Suppressors of Cytokine Signaling-2 and -3 in Vivo and in Vitro

Pituitary Research Unit (G.M.L., J.B., N.D., K.S., K.K.Y.H., K.-C.L.), Garvan Institute of Medical Research, and Department of Endocrinology (K.K.Y.H.), St. Vincent’s Hospital, Sydney, New South Wales 2010, Australia; Center for Bone Research at the Sahlgrenska Academy (S.M., K.S., C.O.), Division of Endocrinology, Department of Internal Medicine, Göteborg University, Göteborg SE-41345, Sweden; and Departments of Medical Nutrition and Bioscience (K.D.-W., J.-Å.G.), Karolinska Institute, Novum, Huddinge SE-14186, Sweden

Address all correspondence and requests for reprints to: Dr. Kin-Chuen Leung, Pituitary Research Unit, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia. E-mail: k.leung{at}garvan.org.au.

Suppressors of cytokine signaling (SOCS) are important negative regulators of cytokine action. We recently reported that estrogen stimulates SOCS-2 expression and inhibits GH signaling in kidney cells. The effects of estrogen on SOCS expression in other tissues are unclear. The aim of this study was to investigate in vivo and in vitro whether estrogen affected SOCS expression in the liver, a major target organ of GH. The in vivo hepatic effects of estrogen on ovariectomized mice lacking estrogen receptor (ER)-, ERß, or both and their wild-type littermates were examined by DNA microarray analysis. In vitro, the effects of estrogen on SOCS expression in human hepatoma cells were examined by reverse transcription quantitative PCR. Long-term (3 wk) estrogen treatment induced a 2- to 3-fold increase in hepatic expression of SOCS-2 and -3 in wild-type and ERß knockout mice but not in those lacking ER or both ER subtypes. Short-term treatment (at 24 h) increased the mRNA level of SOCS-3 but not SOCS-2. In cultured hepatoma cells, estrogen increased SOCS-2 and -3 mRNA levels by 2-fold in a time- and dose-dependent manner (P < 0.05). Estrogen induced murine SOCS-3 promoter activity by 2-fold (P < 0.05) in constructs containing a region between nucleotides –1862 and –855. Moreover, estrogen and GH had additive effects on the SOCS-3 promoter activity. In summary, estrogen, via ER, up-regulated hepatic expression of SOCS-2 and -3, probably through transcriptional activation. This indicates a novel mechanism of estrogen regulation of cytokine action.

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