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Keywords:

  • nitric oxide;
  • inducible nitric oxide synthase;
  • cytokine;
  • mitogen-activated protein kinase;
  • NF-κB;
  • astroglia

Abstract

Expression of inducible nitric oxide synthase (iNOS), which leads to the production of nitric oxide (NO), is stimulated by proinflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Here we report on the roles of nuclear factor-κB (NF-κB) and mitogen-activated protein (MAP) kinases in IL-1β/TNF-α–induced iNOS expression in adult rat astroglia. Cytokine-induced increases in nitrite accumulation (an index of NO production) and iNOS expression were attenuated by inhibition of NF-κB with pyrrolidine dithiocarbamate (PDTC). Similar attenuation of these cytokine-induced responses was produced by inhibition of MAP kinase (MEK), the immediate upstream activator of Erk, using PD098,059. Combined treatment of astroglia with PDTC and PD098,059 completely abolished the cytokine-induced increases in iNOS expression and nitrite accumulation. By contrast, the selective p38 kinase inhibitor SB203,580 amplified the effects of IL-1β/TNF-α on nitrite accumulation. In accordance with these findings, IL-1β– and TNF-α–induced a time-dependent increase in Erk1/Erk2 activation. This cytokine action was completely abolished by PD098,059 but was not altered by PDTC. Finally, IL-1β and TNF-α induced degradation of NF-κB's bound inhibitory protein, IκB-α, leading to translocation of NF-κB into the nucleus. IκB-α expression was not restored to control levels by inhibition of MEK. Furthermore, inhibition of MEK with PD098,059 did not alter IL-1β– and TNF-α–induced expression of active NF-κB. The results demonstrate that autonomous Erk and NF-κB pathways mediate cytokine-induced increases in iNOS expression in astroglia. GLIA 41:152–160, 2003. © 2003 Wiley-Liss, Inc.