Direct regulation of pituitary proopiomelanocortin by STAT3 provides a novel mechanism for immuno-neuroendocrine interfacing

Neuroendocrine ACTH secretion responds to peripheral inflammatory and stres s signals. We previously demonstrated that the proinflammatory cytokine, le ukemia inhibitory factor (LIF), affects the hypothalamo-pituitary-adrenal a xis (HPA) by stimulating in vitro and in vivo pituitary proopiomelanocortin (POMC) gene expression and ACTH secretion and by potentiating the action o f hypothalamic corticotropin releasing hormone (CRH). Whereas pathways show n thus far to regulate POIR-IC expression exclusively involve cAMP or calci um, we here describe a direct and indirect STAT3-dependent regulation of PO MC transcription by LIF. Using progressive 5'-deletions of POMC promoter, w e identified a LIF-responsive -407/-301 region that contains two juxtaposed sequences within -399/-379 related to a STAT3 DNA-binding motif. Each sequ ence within -399/-379 separately corresponds to a low-affinity and direct b inding site for STAT3, but, in combination, these sequences bind STAT3 coop eratively 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 a ctivation of POMC transcription. Demonstration of STAT3-dependent regulatio n of the POMC gene represents a powerful mechanism for immuno-neuroendocrin e interfacing and implies a direct stimulation of ACTH secretion by inflamm atory and stress-derived STAT3-inducing cytokines.