Cytokine-stimulated inducible nitric oxide synthase expression in astroglia: Role of Erk mitogen-activated protein kinase and NF-κB
Article first published online: 28 DEC 2002
Copyright © 2003 Wiley-Liss, Inc.
Volume 41, Issue 2, pages 152–160, 15 January 2003
How to Cite
Marcus, J. S., Karackattu, S. L., Fleegal, M. A. and Sumners, C. (2003), Cytokine-stimulated inducible nitric oxide synthase expression in astroglia: Role of Erk mitogen-activated protein kinase and NF-κB. Glia, 41: 152–160. doi: 10.1002/glia.10168
- Issue published online: 28 DEC 2002
- Article first published online: 28 DEC 2002
- Manuscript Accepted: 4 SEP 2002
- Manuscript Received: 24 APR 2002
- University of Florida Undergraduate Scholars Program Awards
- National Institutes of Mental Health (NIMH) Predoctoral Fellowship
- nitric oxide;
- inducible nitric oxide synthase;
- mitogen-activated protein kinase;
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.