Involvement of P38MAP kinase in the induction of nitric oxide synthase in human astrocytes

The present study underlines the importance of p38 mitogen‐activated protein kinase (p38MAPK) in regulating the expression of iNOS in human astroglia. The combination of IL‐1β and IFN‐γ activated p38MAPK and induced the production of NO and the expression of iNOS in human U373MG astroglial cells. SB203580, a specific inhibitor of p38MAPK, and Dp38, a dominant‐negative mutant of p38MAPK, markedly inhibited cytokine‐induced production of NO and expression of iNOS. Next we investigated the role of NF‐κB in the expression of iNOS. Inhibition of cytokine‐induced NF‐κB activation and iNOS expression by SN50, a specific inhibitor of p50 NF‐κB, but not by SN50M, a nonfunctional peptide mutant, does suggest that activation of NF‐κB is necessary for the expression of iNOS. However, SB203580 and Dp38 had no effect on the activation of NF‐κB suggesting that SB203580 and Dp38 inhibit the expression of iNOS without inhibiting the activation of NF‐κB. Next we examined the role of C/EBP‐b in the expression of iNOS. In contrast to the effect of SB203580 and Dp38 on the activation of NF‐κB, both SB203580 and Dp38 markedly inhibited the activation of C/EBP‐b in cytokine‐stimulated cells. Similar to U373MG astrocytoma cells, Dp38 also inhibited cytokine‐induced expression of iNOS and activation of C/EBP‐b but not that of NF‐κB in human primary astroglia. Taken together, these studies suggest that p38MAPK regulates the expression of iNOS in human astroglia by regulating the activation of C/EBP‐b but not that of NF‐κB. Acknowledgements: This study was supported by NIH grants (NS39940 and AG19487).