Pituitary-adrenal axis regulation in CRH-deficient mice

Corticotropin-releasing hormone (CRH)-deficient (knockout (KO)) mice demons trate severely impaired adrenal responses to restraint, ether, and fasting, and lack the normal diurnal glucocorticoid (GC) rhythm. Here, we summarize recent studies determining the role of CRH in augmenting plasma adrenocort icotrophic hormone (ACTH) concentration after glucocorticoid withdrawal and pituitary-adrenal axis stimulation in the context of inflammation. Even th ough GC insufficient, basal pituitary proopiomelanocortin (POMC) mRNA, ACTH peptide content within the pituitary, and plasma ACTH concentrations are n ot elevated in CRH KO mice. POMC mRNA content in CRH KO mice increases foll owing adrenalectomy, and this increase is reversed by GC, but not aldostero ne, replacement. In marked contrast to the increase in POMC mRNA, plasma AC TH does not increase in the CRH KO mice following adrenalectomy. Administra tion of CRH to adrenalectomized CRH KO mice results in acute, robust ACTH s ecretion. Thus, loss of GC feedback can increase POMC gene expression in th e pituitary, but CRH action is essential for increased secretion of ACTH in to the circulation. While GC secretion is impaired in CRH KO mice after mos t stimuli, we have found near-normal GC responses to inflammation and syste mic immune challenge. Studies in mice with CRH and IL-6 deficiency reveal t hat IL-6 is essential for activation of the pituitary-adrenal axis during i nflammatory and other stressors in the absence of CRH.