Direct regulation of pituitary proopiomelanocortin by STAT3 provides a novel mechanism for immuno-neuroendocrine interfacing
Corinne Bousquet, Maria Chiara Zatelli, Shlomo Melmed
Corinne Bousquet, Maria Chiara Zatelli, Shlomo Melmed
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Direct regulation of pituitary proopiomelanocortin by STAT3 provides a novel mechanism for immuno-neuroendocrine interfacing

Abstract

Neuroendocrine ACTH secretion responds to peripheral inflammatory and stress signals. We previously demonstrated that the proinflammatory cytokine, leukemia inhibitory factor (LIF), affects the hypothalamo-pituitary-adrenal axis (HPA) by stimulating in vitro and in vivo pituitary proopiomelanocortin (POMC) gene expression and ACTH secretion and by potentiating the action of hypothalamic corticotropin releasing hormone (CRH). Whereas pathways shown thus far to regulate POMC expression exclusively involve cAMP or calcium, we here describe a direct and indirect STAT3-dependent regulation of POMC transcription by LIF. Using progressive 5′-deletions of POMC promoter, we identified a LIF-responsive –407/–301 region that contains two juxtaposed sequences within –399/–379 related to a STAT3 DNA-binding motif. Each sequence within –399/–379 separately corresponds to a low-affinity and direct binding site for STAT3, but, in combination, these sequences bind STAT3 cooperatively and with high affinity. Moreover, LIF-activated STAT3 indirectly mediates LIF corticotroph action by inducing and potentiating CRH-induced c-fos and JunB expression and binding to the POMC AP-1 element. We therefore conclude that both a direct and indirect route mediate LIF-induced STAT3 activation of POMC transcription. Demonstration of STAT3-dependent regulation of the POMC gene represents a powerful mechanism for immuno-neuroendocrine interfacing and implies a direct stimulation of ACTH secretion by inflammatory and stress-derived STAT3-inducing cytokines.

Authors

Corinne Bousquet, Maria Chiara Zatelli, Shlomo Melmed

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LIF and CRH are additive for c-fos and JunB mRNA expression. (a) A total...
LIF and CRH are additive for c-fos and JunB mRNA expression. (a) A total of 10 μg total RNA extracted from 1 nM LIF–, 10 nM CRH–, or LIF+CRH–treated AtT20 cells for 30 minutes or 1 hour were separated on a 1% agarose/formaldehyde gel and transferred to nitrocellulose membrane. Hybridization was performed with a 32P-labeled double-stranded DNA probe corresponding to the c-fos, JunB, c-Jun, JunD, Nurr1, Nur77, or β-actin coding sequence, as described previously (23). (b) Northern blot signals for c-fos and JunB mRNA were analyzed by quantitative densitometry and normalized for β-actin. The relative increase of LIF–, CRH–, and LIF+CRH–induced c-fos and JunB mRNA was calculated from three independent experiments (n = 3). NT, vehicle-treated control.