Toll-like receptor 4 plays a crucial role in the immune–adrenal response to systemic inflammatory response syndrome

Abstract

Sepsis and septic shock are leading killers in the noncoronary intensive care unit, and they remain worldwide health concerns. The initial host defense against bacterial infections involves Tolllike receptors (TLRs), which detect and respond to microbial ligands. In addition, a coordinated response of the adrenal and immune systems is crucial for survival during severe inflammation. Previously, we demonstrated a link between the innate immune system and the endocrine stress response involving TLR-2. Like TLR-2, TLR-4 is also expressed in human and mouse adrenals. In the present work, by using a low dose of LPS to mimic systemic inflammatory response syndrome, we have revealed marked cellular alterations in adrenocortical tissue and an impaired adrenal corticosterone response in TLR-4 ؊/؊ mice. Our findings demonstrate that TLR-4 is a key mediator in the crosstalks between the innate immune system and the endocrine stress response. Furthermore, TLR polymorphisms could contribute to the underlying mechanisms of impaired adrenal stress response in patients with bacterial sepsis.lipopolysaccharide ͉ stress axis ͉ sepsis ͉ corticoids ͉ mice

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.…”

“…TLR4-deficient mice have an increased basal cortisol production due to most probably elevated levels of proinflammatory cytokines and marked hyperplasia of the adrenal cortex (Zacharowski et al, 2006). We have tested NCI-H295R cells, since these cells are the only human adrenocortical cell line which expresses all enzymes necessary to synthesize three major adrenal steroids aldosterone, cortisol and DHEA (Rainey et al, 2004).…”

“…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. Since the latter observation was paralleled by dysregulation of plasma cytokines and an impairment of adrenocortical cells ultrastructure an important link between intact TLR expression and a proper adrenal function has been postulated (Zacharowski et al, 2006). …”

Meta-analysis of adrenocortical tumour genomics data: novel pathogenic pathways revealed

“…Several other molecules are required for the recognition of LPS by TLR4 including CD14 and lymphocyte antigen 96 (LY96) (Pa˚lsson-McDermott and O'Neill 2004). TLR4 is expressed on human adrenocortical cells, and it is involved in immuneneuroendocrine crosstalk (Zacharowski et al, 2006). LPS directly stimulates cortisol secretion by NCI-H295 cells (Vakharia and Hinson, 2005), and IL-6 and IL-8 expression by human adrenocortical cells (Kanczkowski et al, 2009).…”

It all happens between Toll receptors and Caspase 1

“…LPS, acting at TLR4-type Toll receptors (5,11,12), induces multiple NF-Bmediated transcriptional changes (13); LPS/TLR4 signaling on its own can induce COX-2, NOS2, and other enzymes that produce inflammatory mediators, such as PGE 2 and NO (14,15). LPS also induces the transcription and synthesis of IL-1␤, TNF-␣, and IL-6 in many cell types and tissues.…”