Molecular Pharmacological studies on the neuron/glia network

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Nitric oxide (NO) is believed to be involved in neurotoxicity after various neuronal stresses and in synaptic plasticity in the cerebellum and thehippocampus in the central nervous system. In the brain, a constitutively expressed NO synthase (cNOS) is expressed in specific neuronal populations, whereit can act as mentioned above. On the other hand, another type of NOS,inducible NOS (iNOS) , is induced by treatment with bacterial endotoxin (lipopolysaccharide, LPS) and/or cytokines in brainglial cells. However, the signal transduction system responsible for induction of iNOS is poorly understood. We examined the induction mechanism of iNOS stimulated by LPS plus interferon-gamma(IFN-gamma) in C6 glioma cells. LPS or IFN-gamma alone could not induce iNOS,but combination of LPS plus IFN-gamma markedly induced iNOS in C6 glioma sells. We found that pretreatment with herbimycin A,apotent selective tyrosine kinase inhibitor, suppressed the induction of NOS by LPS plus IFN-gamma. LPS activated NF-kBand this effect was also sensitive to herbimycin A.On the other hand, IFN-gammastimulated tyrosine-phosphorylation ofJAK2 and STAT1alpha and translocation of STAT1alphato nuclei. These activation by IFN-gamma was also inhibited by herbimycin A.Taken together, these findings suggestthat dual signal transduction pathwaysare required to induce NOS in C6 glioma cells and a tyrosine-kinase is involved in the NF-kB activation.