Activation of acid sphingomyelinase and its inhibition by the nitric oxide/cyclic guanosine 3',5'-monophosphate pathway: key events in Escherichia coli-elicited apoptosis of dendritic cells.

摘要: Depletion of dendritic cells (DCs) via apoptosis contributes to sepsis-induced immune suppression. The mechanisms leading DC during sepsis are not known. In this study we report that immature DCs undergo when treated with high numbers Escherichia coli. This effect was mimicked by concentrations LPS. Apoptosis accompanied generation ceramide through activation acid sphingomyelinase (A-SMase), prevented inhibitors enzyme, and restored exogenous ceramide. Compared DCs, mature expressed significantly reduced levels A-SMase, did generate in response E. coli or LPS, were insensitive coli- LPS-triggered apoptosis. However, sensitivity addition A-SMase Furthermore, inhibition found be the mechanism which immune-modulating messenger NO protects from apoptogenic effects acted formation cGMP stimulation cGMP-dependent protein kinase. relevance its NO/cGMP confirmed a mouse model LPS-induced sepsis. higher inducible synthase-deficient mice than wild-type animals treatment ex vivo NO, cGMP, inhibitor imipramine. Thus, plays central role coli/LPS-induced it might target new therapeutic approaches