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cAMP Neuropeptide Agonists Induce Pituitary Suppressor of Cytokine Signaling-3: Novel Negative Feedback Mechanism for Corticotroph Cytokine Action

Department of Medicine (C.B., V.C., A.K., S.M.), Cedars-Sinai Research Institute-University of California Los Angeles School of Medicine, Los Angeles, California 90048; and Institut National de la Santé et de la Recherche Médicale (INSERM) U531 (C.B., A.F.), Centre Hospitalo-Universitaire Rangueil, 31403 Toulouse, France

Address all correspondence and requests for reprints to: Dr. Shlomo Melmed, Academic Affairs, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Room 2015, Los Angeles, California 90048. E-mail: melmed{at}csmc.edu

The hypothalamo-pituitary-adrenal (HPA) axis maintains a homeostatic response to stress, infection, or neoplasia. Inflammatory cytokines, including leukemia inhibitory factor (LIF), stimulate the HPA axis either directly at the pituitary corticotroph, or indirectly through induction of CRH or sympathetic noradrenergic neurons, and mediate the immuno-neuroendocrine interface. Unrestrained HPA axis activation leads, however, to immunosuppression. Because suppressor of cytokine signaling-3 (SOCS-3) is a potent inhibitor of LIF-activated HPA axis, and dynamic interactions between hypothalamus-derived cAMP-inducing neuropeptides and proinflammatory cytokines occur at the corticotroph level, we investigated SOCS-3 expression in response to peptides that stimulate cAMP including CRH, pituitary adenylate cyclase-activating polypeptide, and epinephrine. (Bu)₂cAMP mediates induction of SOCS-3 promoter activity (6.7-fold ± 0.5, P < 0.001) and SOCS-3 gene expression (4-fold ± 0.8, P < 0.005) in a PKA-dependent manner. LIF and cAMP-inducing agents are additive on SOCS-3 promoter activity (22-fold ± 2.6, LIF + (Bu)₂cAMP vs. 7.3-fold ± 0.6, LIF alone, P < 0.05) and on SOCS-3 transcription (11.3-fold ± 2.1, LIF + (Bu)₂cAMP vs. 9.3-fold ± 1, LIF alone, P < 0.05), suggesting alternate pathways for LIF and cAMP-mediated corticotroph signaling. Similarly, LIF and CRH or pituitary adenylate cyclase-activating polypeptide are additive for SOCS-3 promoter activity and transcription (P < 0.05). Whereas signal transducer and activator of transcription 3 binding to the SOCS-3 promoter mediates LIF action, several SOCS-3 promoter regions containing cAMP-responsive elements are required for cAMP-PKA effect. Thus, both classes of POMC-inducing agents, cytokines as well as cAMP-inducing central peptides, regulate SOCS-3, providing a further level of negative HPA axis control during inflammation. These results indicate a sensitive intracellular autoregulation of corticotroph function.

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