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pubmed-article:8195701pubmed:abstractTextThe highly regulated enzyme HMG-CoA reductase generates mevalonate, the precursor of a complex series of isoprenoids that posttranslationally modify (isoprenylate) certain proteins (e.g., the low-molecular-weight GTP-binding proteins) or that are incorporated into cholesterol and other end products. We recently reported that isoprenoids are required for NADPH oxidase activity in granulocytes via LMW GTP-binding protein isoprenylation. In this study, we evaluated the effects of isoprenoid depletion on the expression of proinflammatory genes in human monocytic THP-1 cells. We selected conditions under which pretreatment for 24 h with isoprenoid synthesis inhibitors (HMG-CoA reductase inhibitor lovastatin or compactin at 10 microM) did not compromise cell viability but markedly suppressed H2O2 generation. Under these conditions interleukin-8 (IL-8) production was attenuated (by 50-90%) in response to lipopolysaccharide, granulocyte-macrophage colony-stimulating factor, and phorbol myristate acetate. Coincubation of reductase inhibitor-treated cells with mevalonate prevented the attenuation of IL-8 production by reductase inhibitors. The effects of isoprenoid depletion on cytokine production were selective: IL-1 beta generation was not inhibited but the production of IL-6 and IL-8 was concomitantly suppressed. IL-8 induction was suppressed at least in part through attenuation of the increase in mRNA in stimulated cells. We conclude that isoprenoid generation through the mevalonate pathway is a requirement for IL-8 induction by activated monocytic cells in vitro. Isoprenylation inhibitors have the potential to alter monocyte proinflammatory function.lld:pubmed
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pubmed-article:8195701pubmed:dateRevised2007-11-15lld:pubmed
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pubmed-article:8195701pubmed:articleTitleRole of the mevalonate pathway of isoprenoid synthesis in IL-8 generation by activated monocytic cells.lld:pubmed
pubmed-article:8195701pubmed:affiliationVeterans Affairs Medical Center, San Diego, California 92161.lld:pubmed
pubmed-article:8195701pubmed:publicationTypeJournal Articlelld:pubmed
pubmed-article:8195701pubmed:publicationTypeResearch Support, U.S. Gov't, P.H.S.lld:pubmed
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