Corticotropin-releasing hormone regulates IL-6 expression during inflammation

J Clin Invest. 2001 Oct;108(8):1159-66. 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adrenalectomy
  • Adrenocorticotropic Hormone / antagonists & inhibitors
  • Adrenocorticotropic Hormone / blood
  • 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


  • Interleukin-6
  • Irritants
  • Adrenocorticotropic Hormone
  • Corticotropin-Releasing Hormone
  • Corticosterone
  • Turpentine