Corticotropin-releasing hormone regulates IL-6 expression during inflammation

Stimulation of the hypothalamic-pituitary-adrenal (HPA) axis by proinflamma tory cytokines results in increased release of glucocorticoid that restrain s 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 cortico tropin-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 inflamma tion CRE is required for a normal adrenocorticotropin hormone (ACTH) increa se but not for adrenal corticosterone rise. The paradoxical increase of pla sma IL-6 associated with CRH deficiency suggests that IL-6 release during i nflammation is CRH-dependent. We also demonstrate that adrenal IL-6 express ion is CRH-dependent, as its basal and inflammation-induced expression is b locked 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(-/-)/I L-6(-/-) mice. These findings, along with the regulation of IL-6 by CRH, su pport the importance of the interaction between the immune system and the H PA axis in the pathophysiology of inflammatory diseases.