cAMP neuropeptide agonists induce pituitary suppressor of cytokine signaling-3: novel negative feedback mechanism for corticotroph cytokine action.
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.
Bousquet
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Department of Medicine, Cedars-Sinai Research Institute-University of California Los Angeles School of Medicine, Los Angeles, California 90048, USA.
Chesnokova
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Kariagina
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Ferrand
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Melmed
S
S
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology*; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004837:Epinephrine / Q000494:pharmacology; D025461:Feedback, Physiological; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006131:Growth Inhibitors / Q000378:metabolism / Q000494:pharmacology; D007031:Hypothalamus / Q000378:metabolism; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009479:Neuropeptides / Q000819:agonists* / Q000494:pharmacology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D010913:Pituitary-Adrenal System / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011506:Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins; D020218:Response Elements; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D014407:Tumor Cells, Cultured
C495402:Adcyap1 protein, mouse; D006131:Growth Inhibitors; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D008222:Lymphokines; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011506:Proteins; D012097:Repressor Proteins; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D015124:8-Bromo Cyclic Adenosine Monophosphate; D003994:Bucladesine; D011333:Pro-Opiomelanocortin; D003346:Corticotropin-Releasing Hormone; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D004837:Epinephrine