Interleukin-6 is an essential, corticotropin-releasing hormone-independent stimulator of the adrenal axis during immune system activation

Abstract

Glucocorticoids play a critical role in control of the cytokine response after immune challenge. Conversely, cytokines modulate glucocorticoid production by the hypothalamic-pituitary-adrenal axis. To define the potency and mechanism of interleukin-6 (IL-6) for augmentation of adrenal function, we exploited mice deficient in corticotropin-releasing hormone (CRH), IL-6, or both. Mice deficient in CRH action demonstrate severely impaired glucocorticoid production in response to psychological and metabolic challenge, but near normal responses to stressors that activate the immune system. In this paper, we demonstrate that IL-6 is essential for activation of the hypothalamic-pituitary-adrenal axis during immunological challenge in the absence of hypothalamic input from CRH. IL-6 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 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. A second model of immune system activation using 2C11, an antibody to the T cell receptor, demonstrated 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 utility of further analysis of IL-6 in determining the female predominance seen in many human inflammatory͞autoimmune diseases. T he 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 (3-6). The importance of the hypothalamic-pituitary-adrenal (HPA) axis and glucocorticoids in modifying the inflammatory and cytokine response is highlighted by studies in adrenalectomized animals (7-9). Adrenalectomized rodents demonstrate increased mortality after injection 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 inflammatio...

COX-2 inhibition attenuates anorexia during systemic inflammation without impairing cytokine production

“…Stimulation of adrenal glucocorticoid release during inflammation reflects actions of cytokines at central nervous system, pituitary, and adrenal sites and provides a useful integrated measure of stimulation and damping of the inflammatory response (3,5,23,38). LPS administration resulted in marked elevation of plasma corticosterone concentrations at 3 h that was sustained at 16 h after administration (Fig.…”

“…Blood was collected on ice, and plasma was separated by centrifugation and stored at Ϫ80°C until assay. Plasma concentration of corticosterone (ICN Biomedicals, Costa Mesa, CA) was determined by radioimmunoassay as previously described (3,13). Plasma concentrations of IL-6 (Pharmingen, San Diego, CA) and leptin (R & D Systems, Minneapolis, MN) were measured by ELISA per the manufacturer's instructions.…”

Discontinuation of BCG Vaccination Precedes Significant Drop in Type 2 Diabetes in Japanese Children. Role of Inflammation and Cortisol Activity as a Cause of Type 2 Diabetes

“…Vaccines have been shown to cause cortisol release [23][24][25][26][27][28][29][30]. This can be explained because vaccines cause the release of IL-6 [31][32][33] an cytokine that causes cortisol release [34][35][36]. Japanese have increased cortisol secretion following immunization compared to Whites [37] and this explains why Japanese have higher rates of type 2 diabetes but lower rates of type 1 diabetes than Whites [4,11,38,39].…”

Interleukin-6 primarily produced by non-hematopoietic cells mediates the lipopolysaccharide-induced febrile response

“…However, the release of stress hormones may differ. Thus, plasma corticosterone levels in mice devoid of IL-6 have been reported to be significantly lower than in wild-type mice (Bethin et al, 2000;van Enckevort et al, 2001), although conflicting data exist (Fattori et al, 1994;Kozak et al, 1998). Hence, it cannot be excluded that a different neuroendocrine environment in the mice on a KO background could have influenced the response of hematopoietic cells and their IL-6 release.…”