Role of the mevalonate pathway of isoprenoid synthesis in IL-8 generation by activated monocytic cells.
The 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.
Terkeltaub
R
R
Veterans Affairs Medical Center, San Diego, California 92161.
Solan
J
J
Barry
M
M
Santoro
D
D
Bokoch
G M
GM
D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000096:biosynthesis; D015870:Gene Expression / Q000187:drug effects*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016209:Interleukin-8 / Q000096:biosynthesis*; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D017368:Protein Prenylation / Q000187:drug effects*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016209:Interleukin-8; C012258:mevastatin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D008148:Lovastatin; D019204:GTP-Binding Proteins; D013755:Tetradecanoylphorbol Acetate; D008798:Mevalonic Acid