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Role of the mevalonate pathway of isoprenoid synthesis in IL‐8 generation by activated monocytic cells
Author(s) -
Terkeltaub Robert,
Solan Joell,
Barry Michael,
Santoro Denise,
Bokoch Gary M.
Publication year - 1994
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.55.6.749
Subject(s) - biology , geranylgeraniol , monocyte , mevalonic acid , mevalonate pathway , reductase , prenylation , proinflammatory cytokine , biochemistry , hmg coa reductase , terpenoid , enzyme , immunology , inflammation
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 μ M) did not compromise cell viability but markedly suppressed H 2 O 2 generation. Under these conditions interleukin‐8 (IL‐8) production was attenuated (by 50–90%) in response to lipopolysaccharide, granulocyte‐macrophage colonystimulating 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 β 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. J. Leukoc. Biol. 55: 749–755; 1994.