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Hormonal Regulation of Suppressors of Cytokine Signaling (SOCS) Messenger Ribonucleic Acid in the Arcuate Nucleus during Late Pregnancy

Centre for Neuroendocrinology and Department of Anatomy and Structural Biology, University of Otago School of Medical Sciences, Dunedin 9054, New Zealand

Address all correspondence and requests for reprints to: Assoc. Prof. Dave Grattan, Centre for Neuroendocrinology and Department of Anatomy and Structural Biology, University of Otago School of Medical Sciences, P.O. Box 913, Dunedin 9054, New Zealand. E-mail: dave.grattan{at}anatomy.otago.ac.nz.

Prolactin stimulates tuberoinfundibular dopamine neurons in the arcuate nucleus of the hypothalamus, mediated by signal transducer and activator of transcription 5b (STAT5b). During late pregnancy, these neurons become unresponsive to prolactin, with a loss of prolactin-induced activation of STAT5b and decreased dopamine secretion. Suppressors of cytokine signaling (SOCS) proteins inhibit STAT-mediated signaling, and SOCS mRNAs are specifically elevated in the arcuate nucleus during late pregnancy. We hypothesized that changes in circulating ovarian steroids during late pregnancy might induce expression of SOCS mRNAs, thus disrupting STAT5b-mediated prolactin signaling. Rats were ovariectomized on d 18 of pregnancy and treated with ovarian steroids to simulate an advanced, normal, or delayed decline in progesterone. Early progesterone withdrawal caused an early increase in prolactin secretion, and increased SOCS-1 and -3 and cytokine-inducible SH2-containing protein (CIS) mRNA levels in the arcuate nucleus. Prolonged progesterone treatment prevented these changes. To determine whether ovarian steroids directly alter SOCS mRNA levels, estrogen- and/or progesterone-treated ovariectomized nonpregnant rats were acutely injected with prolactin (300 µg sc) or vehicle. SOCS-1 and -3 and CIS mRNA levels in the arcuate nucleus were significantly increased by estrogen or prolactin, whereas progesterone treatment reversed the effect of estrogen. Results demonstrate that estrogen and prolactin can independently induce SOCS mRNA in the arcuate nucleus and that this effect is negatively regulated by progesterone. This is consistent with the hypothesis that declining progesterone and high levels of estrogen during late pregnancy induce SOCS in the tuberoinfundibular dopamine neurons, thus contributing to their insensitivity to prolactin at this time.