Cytokine-induced cell death in immortalized Schwann cells: roles of nitric oxide and cyclic AMP.
Tumor necrosis factor-alpha and interferon-gamma are pleiotropic cytokines that regulate Schwann cell responses during injury and inflammatory demyelination. We have previously shown that cyclic AMP (cAMP)-elevating agents decrease the demyelination and Wallerian degeneration in experimental allergic neuritis. In this study, we examined the role of cAMP in cytokine-mediated signaling in a spontaneously immortal Schwann cell clone (iSC). We found that tumor necrosis factor-alpha and interferon-gamma exert synergistic inhibitory action on Schwann cell viability via the production of nitric oxide (NO) and ceramide (cer). Furthermore, we found that: (i) NO synthase inhibitors attenuate the cytokine-induced cer accumulation and cell death indicating that NO acts upstream of cer; and (ii) cytokine-induced cell death is decreased in iSCs pretreated continuously for 48-72 h with forskolin, an activator of adenylate cyclase. Although forskolin modulates the phosphorylation of ERKs and Akt, it decreases the susceptibility of iSC to cytokines via a separate mechanism operating after NO induction and before cer accumulation. We propose that the protective effect of cAMP-elevating agents in experimental allergic neuritis may be mediated in part via modulation of Schwann cell responses to cytokines.
Nagano
S
S
Department of Neurology and Communication on Neurobiology, The Brain Research Institute, The University of Chicago, Illinois 60637, USA.
Takeda
M
M
Ma
L
L
Soliven
B
B
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D002518:Ceramides / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003711:Demyelinating Diseases / Q000201:enzymology / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020275:Guillain-Barre Syndrome / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D015213:Neuroimmunomodulation / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D012583:Schwann Cells / Q000166:cytology* / Q000201:enzymology / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D002518:Ceramides; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D014409:Tumor Necrosis Factor-alpha; D005576:Colforsin; D009569:Nitric Oxide; D007371:Interferon-gamma; D000242:Cyclic AMP; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D019331:NG-Nitroarginine Methyl Ester