Impaired adrenal stress response in Toll-like receptor 2-deficient mice

Abstract

Septicemia is one of the major health concerns worldwide, and rapid activation of adrenal steroid release is a key event in the organism's first line of defense during this form of severe illness. The family of Toll-like receptors (TLRs) is critical in the early immune response upon bacterial infection, and TLR polymorphisms are frequent in humans. Here, we demonstrate that TLR-2 deficiency in mice is associated with reduced plasma corticosterone levels and marked cellular alterations in adrenocortical tissue. TLR-2-deficient mice have an impaired adrenal corticosterone release after inflammatory stress induced by bacterial cell wall compounds. This defect appears to be mediated by a decrease in systemic and intraadrenal cytokine expression, including IL-1, tumor necrosis factor ␣, and IL-6. Our data demonstrate a link between the innate immune system and the endocrine stress response. The critical role of TLR-2 in adrenal glucocorticoid regulation needs to be considered in patients with inflammatory disease.endotoxemia ͉ inflammation ͉ glucocorticoids ͉ immune response

Upregulation of TLR2 and TLR4 in the human adrenocortical cells differentially modulates adrenal steroidogenesis

“…TLR2 and TLR4 in liver (Tsujimoto et al, 2005) or TLR2, TLR4 and TLR9 in peripheral blood (Brandl et al, 2005). This finding is in line with our previous results showing an upregulation of TLR2 and TLR4 in the adrenal glands of mice after injection of lipotechonic acid and LPS (Bornstein et al, 2004b;Zacharowski et al, 2006). In order to see whether an increased expression of TLRs in adrenocortical cells may impact adrenal steroidogenesis, we have stably transfected NCI-H295R cell with expression plasmid encoding either for TLR2 or TLR4-CD14 and tested basal and AII or FSK-stimulated hormone synthesis in these transfected cells.…”

“…We have previously shown expression of several TLRs in mouse and human adrenal glands and in primary cultures of adrenocortical cells (Bornstein et al, 2004a;Kanczkowski et al, 2009). Moreover, we found that TLR2, TLR4 or TLR9 ligands when administered to mice induce a strong systemic and local inflammation of adrenal gland with upregulation of the major proinflammatory cytokines such as IL-1 , IL-6 and TNF- (Bornstein et al 2004b) Interestingly, in the latter study we have found un upregulation of both TLR2 and TLR4 expression in the adrenal glands from mice that received a single dose of LPS or lipoteichonic acid (Bornstein et al, 2004b). However, we also found that TLR2 and TLR4 deficiency results in a dysregulation of adrenal glucocorticoid production and increased mortality of TLR2 and TLR4 deficient mice.…”

Dissociation of Analgesic and Hormonal Responses to Forced Swim Stress Using Opioid Receptor Knockout Mice

“…The former feature is well documented, at least in the rat, and suggests a higher responsiveness of adrenal cortex to ACTH in females (see Atkinson and Waddell, 1997 and references therein;Spinedi et al, 1997). Supporting this hypothesis, TLR2À/À mutant mice that bear an impaired adrenal gland display higher ACTH but decreased corticosterone basal levels (Bornstein et al, 2004). The latter aspect can also be explained by this mechanism, where less ACTH is required to achieve a given corticosterone response.…”

Critical illness-related corticosteroid insufficiency (CIRCI): a narrative review from a Multispecialty Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM)

“…Likewise, IL-1 and its receptor are also produced in the adrenal glands and contribute to steroidogenesis at least partly by regulating prostaglandin pathways [47]. Toll-like receptors (TLR), mainly TLR2 and TLR4, are expressed in the adrenal glands and play a critical role in the local immune-endocrine crosstalk in LPS-challenged rodents [48,49]. Further experiments using genetically manipulated mice suggest that immune cells and not steroid-producing cells are key regulators of the immune-endocrine local interaction [49].…”