Corticotropin-releasing hormone regulates IL-6 expression during inflammation

• Published in: The Journal of clinical investigation 2001-10, Vol.108 (8), p.1159-1166
• Main Authors: Venihaki, M, Dikkes, P, Carrigan, A, Karalis, K P
• Format: Article
• Language: English
• Subjects: Adrenalectomy; Adrenocorticotropic Hormone - antagonists & inhibitors; Adrenocorticotropic Hormone - blood; adrenocorticotropin; Animals; Corticosterone - blood; Corticotropin-Releasing Hormone - deficiency; Corticotropin-Releasing Hormone - genetics; Corticotropin-Releasing Hormone - physiology; Gene Expression Regulation; Hypothalamo-Hypophyseal System - physiology; Inflammation - etiology; Inflammation - immunology; Inflammation - pathology; Inflammation - physiopathology; Interleukin-6 - blood; Interleukin-6 - genetics; Irritants - toxicity; Mice; Mice, Inbred C57BL; Mice, Knockout; Pituitary-Adrenal System - physiology; Turpentine - toxicity
• ISSN: 0021-9738
• DOI: 10.1172/jci12869

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.