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 respon se to stress, infection, or neoplasia. Inflammatory cytokines, including le ukemia inhibitory factor (LIF), stimulate the HPA axis either directly at t he pituitary corticotroph, or indirectly through induction of CRH or sympat hetic noradrenergic neurons, and mediate the immuno-neuroendocrine interfac e. Unrestrained HPA axis activation leads, however, to immunosuppression. B ecause suppressor of cytokine signaling-3 (SOCS-3) is a potent inhibitor of LIF-activated HPA axis, and dynamic interactions between hypothalamus-deri ved cAMP-inducing neuropeptides and proinflammatory cytokines occur at the corticotroph level, we investigated SOCS-3 expression in response to peptid es that stimulate cAMP including CRH, pituitary adenylate cyclase-activatin g polypeptide, and epinephrine. (BU)(2)cAMP mediates induction of SOCS-3 pr omoter 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 )(2)cAMP vs. 7.3-fold +/- 0.6, LIF alone, P < 0.05) and on SOCS-3 transcrip tion (11.3-fold +/- 2.1, LIF + (Bu)(2)cAMP vs. 9.3-fold +/- 1, LIF alone, P < 0.05), suggesting alternate pathways for LIF and cAMP-mediated corticotr oph signaling. Similarly, LIF and CRH or pituitary adenylate cyclase-activa ting polypeptide are additive for SOCS-3 promoter activity and transcriptio n (P < 0.05). Whereas signal transducer and activator of transcription 3 bi nding to the SOCS-3 promoter mediates LIF action, several SOCS-3 promoter r egions containing cAMP-responsive elements are required for cAMP-PKA effect . Thus, both classes of POMC-inducing agents, cytokines as well as cAMP-ind ucing central peptides, regulate SOCS-3, providing a further level of negat ive HPA axis control during inflammation. These results indicate a sensitiv e intracellular autoregulation of corticotroph function.