administration of IL-6 results in a significant rise of plasma ACTH in both WT and CRH KO mice

administration of IL-6 results in a significant rise of plasma ACTH in both WT and CRH KO mice. receptors are present on pituitary corticotrophs and adrenocortical cells, consistent with the ability of IL-6 to bypass CRH in augmentation of adrenal function. Plasma corticosterone Rabbit polyclonal to JNK1 levels after bacterial lipopolysaccharide injection in mice deficient in CRH or IL-6 were significantly lower than in wild-type mice but significantly greater than in mice deficient in both CRH and IL-6. BMS-1166 hydrochloride A second model of immune system activation using 2C11, an antibody to the T cell receptor, exhibited a normal corticosterone response in mice deficient in CRH or IL-6, but a markedly decreased response in mice deficient in both CRH and IL-6. Surprisingly, the relative contribution of IL-6 for modulation of the adrenal response to stress is greater in female than in male mice. This gender-specific difference in IL-6 action in mice suggests the power of further analysis of IL-6 in determining the female predominance seen in many human inflammatory/autoimmune diseases. The nervous, endocrine, and immune systems interact to maintain physiological homeostasis during inflammation and stressors that induce systemic cytokine production (1, 2). Corticotropin-releasing hormone (CRH), synthesized in the hypothalamus, is the major secretagogue regulating pituitary adrenocorticotropin (ACTH) release and adrenal glucocorticoid production. CRH also modulates stress-induced autonomic, behavioral, and local inflammatory responses (3C6). The importance of the hypothalamicCpituitaryCadrenal (HPA) axis and glucocorticoids in modifying the inflammatory and cytokine response is usually highlighted by studies in adrenalectomized animals (7C9). Adrenalectomized rodents demonstrate increased mortality after injection BMS-1166 hydrochloride of bacterial lipopolysaccharide (LPS), interleukin (IL)-1, or tumor necrosis factor (TNF)-. With glucocorticoid administration, adrenalectomized mice survive. LPS-injected, adrenalectomized mice also demonstrate higher plasma levels of IL-1 and TNF-. Elevation of plasma glucocorticoids results in suppression of cytokines such as IL-1, IL-6, and TNF- and in up-regulation of other cytokines, such as IL-4 and IL-10, and cytokine receptors (1, 2, 7, 8, 10). Thus, by regulation of cytokine production and action, the HPA axis contributes to modulation of the response to inflammation. Initial studies in CRH-deficient knockout (KO) mice revealed markedly attenuated glucocorticoid production after restraint, ether, and fasting stressors as compared with CRH-intact mice (11, 12). In contrast, inflammatory stress induced by the seaweed polysaccharide, carrageenan, demonstrated that CRH KO male mice are able to significantly increase plasma corticosterone, although to a lesser degree than wild-type (WT) mice (13). Recent characterization of mice deficient in CRH receptor type 1 (Crhr1) (14, 15) has further highlighted the dichotomy in regulation of glucocorticoid production in response to inflammatory versus noninflammatory stressors. For example, plasma corticosterone levels in Crhr1 KO mice were significantly less than those of WT mice after forced-swim stress BMS-1166 hydrochloride (15). After local inflammation caused by turpentine injection, however, Crhr1 KO mice significantly increased plasma corticosterone, approaching levels achieved in WT mice (16). The ability of inflammation to significantly augment serum glucocorticoid concentrations impartial of CRH action around the pituitary Crhr1 confirms that immune system activation during the inflammatory response has the capacity to stimulate the HPA axis by CRH receptor-independent mechanisms. Cytokines released during systemic and localized inflammation elicit a number of responses in the host, including fever, diarrhea, anorexia, and, in severe cases, shock (1, 2, 8, 17). Among those cytokines released, IL-6, IL-1, and TNF- also demonstrate the ability to stimulate the HPA axis. Several reports on the effects of TNF- on ACTH secretion have shown that the main actions of TNF- are on the hypothalamus and depend on CRH (18, 19). Similarly, IL-1 stimulation of the HPA axis likely results from activation of CRH release (20C22). Further, as exhibited in IL-1 KO mice, the initial rise in plasma corticosterone after induction of local inflammation (turpentine injection) is not affected by deficiency of IL-1 (23). Plasma levels of IL-6 have been shown to rise in response to restraint, electrical foot shock, open-field exposure, systemic immune challenge (LPS), and local inflammation (6, 23, 24). Administration of exogenous IL-6 to rats stimulates ACTH and corticosterone production, and s.c. injection of IL-6 into human cancer patients has been shown to elevate plasma ACTH and cortisol levels (25C28). Induction of IL-6 receptor in the hypothalamic paraventricular nucleus in response to inflammation (29) BMS-1166 hydrochloride suggests that at least part of the ability of IL-6 to augment pituitary and adrenal function occurs by a CRH-dependent mechanism, although CRH-independent actions of IL-6 around the pituitary and adrenal also may occur. Because IL-6 is able to stimulate the HPA axis and perhaps ACTH release directly, we hypothesized that IL-6 is the molecule primarily responsible for augmenting corticotroph and adrenal function in the absence of CRH action around the Crhr1. To conclusively test this hypothesis, we generated mice deficient in both CRH and IL-6 (CRH KO/IL-6 KO) and analyzed their pituitaryCadrenal axis responses to both stressors.