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The Role of Endogenous Interleukin-1 in Stress-Induced Adrenal Activation and Adrenalectomy-Induced Adrenocorticotropic Hormone Hypersecretion

Department of Psychology (I.G., R.Y.), The Hebrew University of Jerusalem, Jerusalem 91905, Israel; Department of Neurochemistry and Neurotoxicology (K.I.), Stockholm University, SE-106 91 Stockholm, Sweden; and Department of Neurology (J.W.), the Agnes Ginges Center for Human Neurogenetics, Hadassah University Hospital, Jerusalem 91120, Israel

Address all correspondence and requests for reprints to: Raz Yirmiya, Ph.D., Department of Psychology, The Hebrew University of Jerusalem, Mount Scopus, Jerusalem 91905, Israel. E-mail: razyirmiya{at}huji.ac.il.

To examine the role of IL-1 in the regulation of the hypothalamo-pituitary-adrenal (HPA) axis, mice with knockout of the IL-1 receptor type I (IL-1rKO) were exposed to psychological and metabolic stressors. When exposed to mild stressors (auditory stress or a low dose of 2-deoxyglucose), IL-1rKO mice displayed a significantly diminished corticosterone secretion, compared with wild-type (WT) controls. In response to more severe stressors (60-min restraint or a high dose of 2-deoxyglucose), both groups exhibited a similar increase in corticosterone secretion. To examine the role of IL-1 in HPA axis feedback regulation, serum ACTH levels were measured after adrenalectomy (ADX) in IL-1rKO mice and in mice with transgenic overexpression of IL-1 receptor antagonist within the brain (IL-1raTG). As expected, WT controls exhibited ADX-induced ACTH hypersecretion, whereas IL-1rKO and IL-1raTG mice showed no increase in ACTH levels, suggesting that brain IL-1 has a critical role in ADX-associated ACTH hypersecretion. Similarly, WT mice that were chronically exposed to IL-1ra in utero displayed a diminished ADX-induced ACTH hypersecretion, compared with vehicle-treated controls, suggesting a developmental role of IL-1 in HPA axis regulation. In conclusion, our results suggest that endogenous IL-1 plays a critical role in HPA axis activation after stress and ADX.

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