Neutral sphingomyelinase inhibitor C11AG prevents lipopolysaccharide-induced macrophage activation.
Stimulation of macrophages by lipopolysaccharide (LPS) leads to the synthesis of proinflammatory cytokines and nitric oxide (NO) and, as a consequence, to endotoxic shock. We provide evidence that LPS stimulates the activity of a membrane-associated neutral sphingomyelinase (nSMase) and that this activity is mandatory for the liberation of nuclear factor-kappa B (NF kappa B) and the induction of inducible NO-synthase (iNOS). With the aid of a newly developed, selective inhibitor of nSMase, C11AG, we could distinguish between nSMase-dependent and -independent LPS-induced signals. C11AG blocked LPS-stimulated sphingomyelin degradation and NF kappa B activation without interfering with p42 tyrosine phosphorylation. Concomitantly, the expression of iNOS was found to be reduced both in mononuclear cells and in murine endotoxemia. Therefore, specific inhibitors of nSMase may define a new class of antiinflammatory substances.
Amtmann
E
E
German Cancer Research Center, Abteilung Immunregulation und Tumorabwehr, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. e.amtmann@dkfz.de
Baader
W
W
Zöller
M
M
D000818:Animals; D002460:Cell Line; D002518:Ceramides / Q000378:metabolism; D019446:Endotoxemia / Q000378:metabolism; D004790:Enzyme Induction; D004926:Escherichia coli; D015870:Gene Expression; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000201:enzymology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D010766:Phosphorylation; D011817:Rabbits; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors* / Q000378:metabolism
C500287:C11AG compound; D002518:Ceramides; D006146:Guanidines; D008070:Lipopolysaccharides; D016328:NF-kappa B; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D020928:Mitogen-Activated Protein Kinases; D013108:Sphingomyelin Phosphodiesterase