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Oxidative Stress Augments the Production of Matrix Metalloproteinase-1, Cyclooxygenase-2, and Prostaglandin E₂ through Enhancement of NF-B Activity in Lipopolysaccharide-Activated Human Primary Monocytes¹

Immunopathology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892

The excessive production of reactive oxidative species (ROS) associated with inflammation leads to a condition of oxidative stress. Cyclooxygenase-2 (COX-2), PGE₂, and matrix metalloproteinases (MMPs) are important mediators during the process of inflammation. In this paper we report on studies examining how the ROS hydrogen peroxide (H₂O₂) affects the production of MMP-1, COX-2, and PGE₂. Addition of H₂O₂ to LPS-activated monocytes, but not naive monocytes, caused a significant enhancement of the LPS-induced production of MMP-1, COX-2, and PGE₂. The mechanism by which H₂O₂ increased these mediators was through enhancement of IB degradation, with subsequent increases in NF-B activation and NF-B p50 translocation to the nucleus. The effects of H₂O₂ on IB degradation, NF-B activation, and NF-B p50 localization to the nucleus were demonstrated through studies of coimmunoprecipitation of IB with p50, ELISA of NF-B p65 activity, and Western blot analysis of the nuclear fraction extract for p50. The key role for NF-B in this process was demonstrated by the ability of MG-132 or lactacystin (proteasome inhibitors) to block the enhanced production of MMP-1, COX-2, and PGE₂. In contrast, indomethacin, which inhibited PGE₂ production, partially blocked the enhanced MMP-1 production. Moreover, although PGE₂ restored MMP-1 production in indomethacin-treated monocyte cultures; it failed to significantly restore MMP-1 production in proteasome inhibitor-treated cultures. Thus, in the presence of LPS and H₂O₂, NF-B plays a dominate role in the regulation of MMP-1, COX-2, and PGE₂ expression.

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