Study On Chloroquine To Prevent And Cure Systemic Inflammatory Response Syndrome Induced By CpG DNA

Objective Systemic inflammatory response syndrome (SIRS), which is a common complication in patients with extensive deep burns and severe traumas, has a high mortality. It is urgent to study on the mechanism and the prevention and cure of SIRS. With over 60 years of clinical practice, chloroquine (CQ) is an effective drug for the treatment of malaria and some autoimmunological disorders such as rheumatoid arthritis and systemic lupus erythematosus. The mechanism by which CQ treat the autoimmunological disorders is likely to associate with its inhibition on monocytes or macrophages to release TNF-??and IL-6. The current study, based on the protective action of CQ on murine SIRS models, is to investigate possible mechanisms for its inhibitory effects on SIRS.Methods â‘  Murine SIRS models, induced by Escherichia coli DNA, CpG ODN, LPS or inactivated Escherichia coli, were established to observe the protective action of CQ. â‘¡ Human peripheral blood mononuclear cells (hPBMC) were isolated and induced by Escherichia coli DNA, CpG ODN or LPS to release TNF-? and IL-6,which were detected by enzyme linked immunosorbent assay (ELISA), the dose- and time-dependent inhibitory role of CQ were observed. â‘¢ Effect of CQ on accumulation of 6-FAM CpG ODN in human monocytes was observed by using flow cytometry to illustrate its inhibitory role on endosomal maturation. â‘£ Inhibition of CQ on activation of NF-?B was observed by using electrophoretic mobility shift assay (EMSA).Results We found that 30 mg/kg of CQ could protect mice from lethal challenge by Escherichia coli DNA, CpG ODN, LPS or inactivated Escherichia coli. In hPBMC, CQ inhibited TNF-? and IL-6 induced by Escherichia coli DNA, CpG ODN or LPS in a dose- and time-dependent manner. Flow cytometry revealed that CQ increased accumulation of 6-FAM CpG ODN within human monocytes, suggesting that the delayed degradation of CpG ODN was associated with the reduction of proinflammatory cytokines release from cells. Furthermore, CQ inhibited the activation of NF-?B induced by Escherichia coli DNA, CpG ODN or LPS. Conclusions Our data indicate a potent anti-inflammatory effect of chloroquine on murine SIRS models. The mechanism may be due to its inhibitory effect on endosomal maturation of monocytes or macrophages, which consequently interfere signaling transduction and inhibit NF-?B activation in cells, and diminish proinflammatory cytokines release at last.