Corticotropin-releasing hormone regulates IL-6 expression during inflammation.
Stimulation of the hypothalamic-pituitary-adrenal (HPA) axis by proinflammatory cytokines results in increased release of glucocorticoid that restrains further development of the inflammatory process. IL-6 has been suggested to stimulate the HPA axis during immune activation independent of the input of hypothalamic corticotropin-releasing hormone (CRH). We used the corticotropin-releasing hormone-deficient (Crh(-/-)) mouse to elucidate the effect of CRH deficiency on IL-6 expression and IL-6-induced HPA axis activation during turpentine-induced inflammation. We demonstrate that during inflammation CRH is required for a normal adrenocorticotropin hormone (ACTH) increase but not for adrenal corticosterone rise. The paradoxical increase of plasma IL-6 associated with CRH deficiency suggests that IL-6 release during inflammation is CRH-dependent. We also demonstrate that adrenal IL-6 expression is CRH-dependent, as its basal and inflammation-induced expression is blocked by CRH deficiency. Our findings suggest that during inflammation, IL-6 most likely compensates for the effects of CRH deficiency on food intake. Finally, we confirm that the HPA axis response is defective in Crh(-/-)/IL-6(-/-) mice. These findings, along with the regulation of IL-6 by CRH, support the importance of the interaction between the immune system and the HPA axis in the pathophysiology of inflammatory diseases.
Venihaki
M
M
Division of Endocrinology, Children's Hospital, Harvard Medical School, 300 Longwood Ave., Boston, MA 02115, USA.
Dikkes
P
P
Carrigan
A
A
Karalis
K P
KP
D000315:Adrenalectomy; D000324:Adrenocorticotropic Hormone / Q000037:antagonists & inhibitors / Q000097:blood; D000818:Animals; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology; D007249:Inflammation / Q000209:etiology* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics*; D007509:Irritants / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010913:Pituitary-Adrenal System / Q000502:physiology; D014425:Turpentine / Q000633:toxicity
D015850:Interleukin-6; D007509:Irritants; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone; D014425:Turpentine