Abstract
Objectives: To investigate the effect of dexamethasone on triggering receptor expressed on myeloid cells-1 (TREM-1).Methods: Wild-type and tumor necrosis factor (TNF−/−) mice were pre-treated with saline, dexamethasone, or hydrocortisone and exposed to a lethal infection of Pseudomonas aeruginosa. Mortality and TREM-1 on neutrophil membranes was measured after sacrifice. U937 human monocytic cells were stimulated with lipopolysaccharide (LPS) or heat-killed P. aeruginosa without or with dexamethasone or hydrocortisone, and cell-surface TREM-1 and soluble TREM-1 (sTREM-1) were quantified. Expression of TREM-1 and sTREM-1 was also studied in LPS-stimulated U937 cells incubated in the absence or presence of TNFα or anti-TNFα antibody.Results: Pre-treatment with dexamethasone, but not hydrocortisone, prolonged animal survival. Mice pre-treated with dexamethasone showed decreased expression of TREM-1 on neutrophils. In U937 cells, LPS or heat-killed P. aeruginosa induced the expression of TREM-1 and the release of sTREM-1. U937 TREM-1 and sTREM-1 were decreased upon addition of dexamethasone but not hydrocortisone. The suppressive effect of dexamethasone was enhanced in the presence of exogenous TNFα and lost in the presence of anti-TNFα antibody. In TNF−/− mice, dexamethasone suppression of mortality and TREM-1 neutrophil expression was lost. Gene expression of TREM-1 in U937 monocytes was decreased after treatment with dexamethasone.Conclusion: TREM-1/sTREM-1 is a novel site of action of dexamethasone. This action is associated with down-regulation of gene expression and is mediated by TNFα.
Highlights
Triggering receptor expressed on myeloid cells-1 (TREM-1) is a transmembrane receptor that is expressed on the membrane of cells of myeloid origin, notably neutrophils and monocytes
Mice pre-treated with dexamethasone showed decreased expression of TREM-1 on neutrophils
Gene expression of TREM-1 in U937 monocytes was decreased after treatment with dexamethasone
Summary
Triggering receptor expressed on myeloid cells-1 (TREM-1) is a transmembrane receptor that is expressed on the membrane of cells of myeloid origin, notably neutrophils and monocytes. TREM-1 stimulation leads to production of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNFα) and interleukin (IL)-8. TREM-1 is shed in the systemic circulation from cell membranes and the soluble receptor, sTREM-1, behaves as an anti-inflammatory mediator [2]. Current evidence suggests that TREM-1/sTREM-1 may be an important player in the pathogenesis of sepsis. TREM-1 activity is thought to be pro-inflammatory and expression of TREM-1 is elevated on circulating neutrophils in patients with septic shock [3]. STREM-1 is considered to possess anti-inflammatory activity, since injection of sTREM-1 protects mice from lethal endotoxic shock [2]. Evidence suggests an anti-inflammatory role of sTREM-1 in human sepsis, since it follows the kinetics of antiinflammatory cytokines [4]. TREM-1/sTREM-1 may be targets for host response modulation in order to offer a survival benefit for the host
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