Cytokine-induced cell death in immortalized Schwann cells: roles of nitricoxide and cyclic AMP

Tumor necrosis factor-alpha and interferon-gamma are pleiotropic cytokines that regulate Schwann cell responses during injury and inflammatory demyeli nation. We have previously shown that cyclic AMP (cAMP)-elevating agents de crease the demyelination and Wallerian degeneration in experimental allergi c neuritis. In this study, we examined the role of cAMP in cytokine-mediate d signaling in a spontaneously immortal Schwann cell clone (iSC). We found that tumor necrosis factor-alpha and interferon-gamma exert synergistic inh ibitory action on Schwann cell viability via the production of nitric oxide (NO) and ceramide (cer). Furthermore; we found that: (i) NO synthase inhib itors attenuate the cytokine-induced cer accumulation and cell death indica ting 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 ac tivator of adenylate cyclase. Although forskolin modulates the phosphorylat ion of ERKs and AM, it decreases the susceptibility of iSC to cytokines via a separate mechanism operating after NO induction and before cer accumulat ion. We propose that the protective effect of cAMP-elevating agents in expe rimental allergic neuritis may be mediated. in part via modulation of Schwa nn cell responses to cytokines.