Effect Of Bms-470539 On Lipopolysaccharide-Induced Neutrophil Activation

Background: BMS-470539, a recently introduced selective agonist of the melanocortin 1 receptor, is known to have anti-inflammatory properties. In this study, we investigated the effects of BMS-470539 on lipopolysaccharide (LPS)-induced inflammatory responses and delayed apoptosis with its signaling pathways in human neutrophils.Methods: Isolated human neutrophils were incubated with various concentrations of BMS-470539 (1, 10, and 100 mu M) in the presence or absence of LPS (100 ng/ml), and the expression of pro-inflammatory cytokines, such as tumor necrosis factor alpha, interleukin (IL)-6, and IL-1 beta, were assessed. The effects of BMS-470539 on the expression of mitogen-activated protein kinases (MAPKs), such as p38, extracellular-signal-regulated kinase 1/2, and c-Jun N-terminal kinase, and the expression of nuclear factor kappa B (NF-kappa B) in LPS-stimulated human neutrophils, were evaluated by enzyme-linked immunosorbent assay. Neutrophil apoptosis was also measured by fluorescence-activated cell sorting (annexin V/propidium iodide) in LPS-stimulated neutrophils under treatment with BMS-470539.Results: BMS-470539 attenuated LPS-induced expression of pro-inflammatory cytokines, and phosphorylation of MAPKs and NF-kappa B. LPS stimulation reduced neutrophil apoptosis compared to the controls; however, BMS-470539 significantly inhibited the reduction of neutrophil apoptosis.Conclusions: BMS-470539 can suppress the inflammatory responses of LPS-stimulated neutrophils by inhibition of MAPK pathways or NF-kappa B pathway, and it can also inhibit LPS-delayed neutrophil apoptosis.