Acid sphingomyelinase-derived ceramide is not required for inflammatory cytokine signalling in murine macrophages.
Sphingomyelin hydrolysis is induced in myeloid cell-lines by tumour necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1beta), and interferon gamma (IFN-gamma). Ceramide, a product of sphingomyelin hydrolysis, recapitulates many of the cellular responses elicited by these cytokines, and this has lead to the hypothesis that ceramide is a second messenger of cytokine signalling. Sphingomyelin hydrolysis is catalysed by an acid spingomyelinase (ASMase) and one or more neutral sphingomyelinases (NSMase); both ASMase and NSMase are activated during cytokine signalling. In the present study, the contribution of ASMase to TNF-alpha, IL-1beta, and IFN-gamma signalling in murine macrophages was addressed. Cytokine-induced responses were compared in macrophages derived from the bone marrow of AMSase null and wild-type mice. Specifically, TNF-alpha-and IFN-gamma-induced nitric oxide production and TNF-alpha- and IL-1beta-induced expression of the alpha-chemokine, KC, were intact in ASMase null macrophages. Furthermore, TNF-alpha induction of p42/p44 ERK and p38-MAPK phosphorylation, c-jun kinase activation, and IkappaBalpha degradation were normal. Also normal in ASMase null macrophages was TNF-alpha-, IL-1beta- and IFN-gamma-induced expression of a panel of early response genes. It is concluded that ASMase is non-essential for the inflammatory signals activated in murine macrophages by TNF-alpha, IL-1beta and IFN-gamma.
Department of Biology, Amgen Inc., Boulder, CO 80301, USA.
C L
CL
Manthey
E H
EH
Schuchman
D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002518:Ceramides / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D020672:I-kappa B Proteins; D007249:Inflammation; D007371:Interferon-gamma / Q000494:pharmacology / Q000502:physiology*; D007375:Interleukin-1 / Q000494:pharmacology / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases; D008264:Macrophages / Q000201:enzymology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D000072000:NF-KappaB Inhibitor alpha; D015398:Signal Transduction / Q000502:physiology*; D013108:Sphingomyelin Phosphodiesterase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases
D002518:Ceramides; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D007375:Interleukin-1; C000606205:Nfkbia protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D007371:Interferon-gamma; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013108:Sphingomyelin Phosphodiesterase