CRF Type I Receptor-Deficient Mice Exhibit a Pronounced Pituitary-Adrenal Response to Local Inflammation

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Abstract
Recent studies indicate that the regulation of adrenocorticotropin (ACTH) secretion by corticotropin-release factor (CRF) is mediated predominantly by the type I CRF receptor (CRF-R1). Indeed, CRF-R1-deficient (CRF-R1 −/−) mice show marked impairment of the pituitary-adrenal axis. However, the plasma ACTH concentrations of unstressed CRF-R1 −/− mice are similar to those in wild-type mice. We show here that arginine vasopressin (AVP) is a major ACTH secretagogue in CRF-R1 −/− mice in resting conditions, since administration of anti-AVP serum, but not anti-CRF serum, markedly reduced (by 60%) resting plasma ACTH concentrations in these mutants. We also investigated the pituitary-adrenal response to turpentine-induced local inflammation in CRF-R1 −/− mice. Administration of turpentine into the hind-limb of CRF-R1 −/− mice produced a slightly (15–25%) smaller swelling of the limb, but a 10 fold greater rse in plasma IL-6 levels, compared to CRF-R1 +/+ controls. Turpentine-induced local inflammation produced pronounced elevations in the plasma concentrations of both ACTH and corticosterone in both CRF-R1 −/− and wild-type mice, but ACTH secretion could be inhibited by anti-CRF and anti-AVP sera only in wild-type mice. These data indicate that resting ACTH secretion in CRF-R1 −/− mice is in part attributable to AVP-dependent mechanisms. Furthermore, while in normal mice the pituitary-adrenal response to local inflammation is mediated largely via CRF-dependent mechanisms, mice deficient in CRF-R1 are still able to mount a pituitary-adrenal response via mechanisms that do not depend critically on either CRF or AVP action.

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