Immunobiology
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Posttrauma apoptosis resistance of neutrophils (PMN) is related to overshooting immune responses, systemic inflammatory response syndrome (SIRS) and multiple organ failure (MOF). Recently, we have shown that the apoptosis resistance in circulating PMN from severely injured patients which is known to be mediated by high serum levels of pro-inflammatory cytokines can be overcome by the activation of Fas death receptor. Here, we aimed to study whether stimulation of surface Fas leads to the inactivation of hyperactivated PMN from critically ill patients with SIRS. ⋯ Thus, in trauma PMN down-regulation of neutrophil activity seems to be delayed when compared to cells isolated from healthy controls, suggesting impaired susceptibility for Fas stimulation in these cells. Interestingly, whereas Fas-mediated inhibition of phagocytosis and oxidative burst could be prevented by the broad range caspase inhibitor t-butoxycarbonyl-aspartyl(O-methyl)-fluoromethyl ketone (BocD-fmk), the chemotactic activity in response to IL-8 was unaffected. In conclusion, we demonstrate that stimulation of neutrophil Fas does not only initiate apoptosis but also induces inhibition of neutrophil functions, partially by non-apoptotic signaling.
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Toll-like receptors (TLRs) have been shown to play a pivotal role in both innate and adaptive immune responses. TLR family is the essential recognition and signaling component of mammalian host defense. Both genetic and biochemical data support a common signaling pathway that finally leads to the activation of NF-κB and induction of the cytokines and co-stimulatory molecules required for the activation of the adaptive immune response. ⋯ The cytokine IL-6 production was significantly increased in ox-LDL treated group and was decreased by quercetin treatment. Quercetin mediated reduction of TLR2 and TLR4 expression and the inhibition of nuclear translocation of NF-κB p65 in turn decreased the inflammatory enzymes like 5-LOX and COX and also decreased the mRNA expression of inducible enzymes like COX-2 and iNOS. Quercetin inhibited the ox-LDL induced TLR2 and TLR4 expression at mRNA level and modulated the TLR-NF-κB signaling pathway thereby inhibited the cytokine production and down regulated the activity of inflammatory enzymes thus have protective effect against the ox-LDL induced inflammation in PBMCs.