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Ceramide and ceramide 1-phosphate are negative regulator sof TNF production induced by lipopolisaccharide

Upon infection, the innate immune system start to combat microorganisms. One of the main factors which activates the immune system is endotoxin – lipopolisaccharide (LPS). LPS is recognized by Toll-like receptor 4 (TLR4) expressed on the surface of cells of the immune system. This interaction induces production of proinflamatory cytokines leading to inflammation. Excessive host responses to LPS may cause life frightening diseases, named septic shock.
In our studies on the mechanisms of activation of macrophages by LPS we found that low doses of LPS strongly activate macrophages and induce intensive production of a proinflamatory cytokine TNF. At higher doses of LPS, TNF production is reduced. Looking for the mechanisms which negatively regulate cellular responses to high concentrations of LPS we found that LPS activates acid and neutral sphingomyelinases. This leads to production of ceramide which is next converted into ceramide 1-phosphate by ceramide kinase. Lowering of acid and neutral activities as well as the activity of ceramide kinase reduced the level of ceramide and ceramide 1-phosphate with concomitant diminishing of TNF production. Similar effects were obtained after silencing of expression of the studies enzymes. Obtained data indicate that ceramide and ceramide 1-phosphate generated in cells challenged with LPS can protect the organism from the endotoxin and limit inflammation.

Date
29 December 2010