CRF type I receptor-deficient mice exhibit a pronounced pituitary-adrenal response to local inflammation

Recent studies indicate that the regulation of adrenocorticotropin (ACTH) s ecretion by corticotropin-releasing 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 pla sma ACTH concentrations of unstressed CRF-RI -/- 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 administr ation of anti-AVP serum, but not anti-CRF serum, markedly reduced (by 60%) resting plasma ACTH concentrations in these mutants. We also investigated t he pituitary-adrenal response to turpentine-induced local inflammation in C RF-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 rise in plasma IL-6 levels, compared to CRF-R1 +/+ controls . Turpentine-induced local inflammation produced pronounced elevations in t he 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 mech anisms. 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 vi a mechanisms that do not depend critically on either CRF or AVP action.