Pituitary-adrenal axis regulation in CRH-deficient mice.
Corticotropin-releasing hormone (CRH)-deficient (knockout (KO)) mice demonstrate 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 adrenocorticotrophic hormone (ACTH) concentration after glucocorticoid withdrawal and pituitary-adrenal axis stimulation in the context of inflammation. Even though GC insufficient, basal pituitary proopiomelanocortin (POMC) mRNA, ACTH peptide content within the pituitary, and plasma ACTH concentrations are not elevated in CRH KO mice. POMC mRNA content in CRH KO mice increases following adrenalectomy, and this increase is reversed by GC, but not aldosterone, replacement. In marked contrast to the increase in POMC mRNA, plasma ACTH does not increase in the CRH KO mice following adrenalectomy. Administration of CRH to adrenalectomized CRH KO mice results in acute, robust ACTH secretion. Thus, loss of GC feedback can increase POMC gene expression in the pituitary, but CRH action is essential for increased secretion of ACTH into the circulation. While GC secretion is impaired in CRH KO mice after most stimuli, we have found near-normal GC responses to inflammation and systemic immune challenge. Studies in mice with CRH and IL-6 deficiency reveal that IL-6 is essential for activation of the pituitary-adrenal axis during inflammatory and other stressors in the absence of CRH.
Muglia
L J
LJ
Dept. of Pediatrics, Washington Univ. School Med., St. Louis, MO 63110, USA.
Bethin
K E
KE
Jacobson
L
L
Vogt
S K
SK
Majzoub
J A
JA
D000315:Adrenalectomy; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D007031:Hypothalamus / Q000378:metabolism; D007107:Immune System / Q000187:drug effects / Q000503:physiopathology; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D010902:Pituitary Gland / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000503:physiopathology*; D011333:Pro-Opiomelanocortin / Q000235:genetics; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000276:immunology; D012016:Reference Values; D014667:Vasopressins / Q000235:genetics
D000906:Antibodies; D015850:Interleukin-6; D008070:Lipopolysaccharides; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D014667:Vasopressins; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone