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The Strathprints institutional repository is a digital archive of University of Strathclyde research outputs. Strathprints provides access to thousands of Open Access research papers by University of Strathclyde researchers, including those from the School of Psychological Sciences & Health - but also papers by researchers based within the Faculties of Science, Engineering, Humanities & Social Sciences, and from the Strathclyde Business School.

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Hydrogen peroxide-mediated inhibition of lipopolysaccharide-stimulated inhibitory kappa b kinase activity in rat aortic smooth muscle cells

Torrie, L.J. and MacKenzie, C. and Paul, A. and Plevin, R.J. (2001) Hydrogen peroxide-mediated inhibition of lipopolysaccharide-stimulated inhibitory kappa b kinase activity in rat aortic smooth muscle cells. British Journal of Pharmacology, 134 (2). pp. 393-401. ISSN 0007-1188

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Abstract

In rat aortic smooth muscle cells (RASMC), exposure to lipopolysaccharide (LPS) resulted in NF-κB-DNA binding, degradation of IκB-α, -β and -ε and increased activity of both α and β isoforms of inhibitory kappa B kinase (IKK). Expression of dominant-negative (DN)-IKK-α, IKK-β and NF-κB-inducing kinase (NIK) abolished LPS-stimulated NF-κB reporter activity, suggesting that activation of a NIK/IKK-dependent pathway is indispensable for NF-κB activation by LPS in this cell type. The tyrosine phosphatase inhibitor, pervanadate, abolished LPS-stimulated NF-κB-DNA-binding activity. However, the effect of pervanadate was shown to be mediated by excess hydrogen peroxide (H2O2) present in the reaction mix. Preincubation of RASMC with H2O2 inhibited LPS-stimulated IKK kinase activity and downstream NF-κB-DNA binding activity. H2O2 also strongly stimulated p38 MAP kinase activity in RASMCs. Effective inhibition of this pathway using SB203580 did not reverse the effects of H2O2 on LPS-stimulated IKK/NF-κB signalling. These studies show that hydrogen peroxide-mediated inhibition of LPS-stimulated NF-κB activation in RASMC occurs upstream of IKK. The inhibitory effect of H2O2 is not due to tyrosine phosphatase inhibition, it is mediated by H2O2 through a mechanism which is independent of any cross-talk involving MAP kinase homologues.