Differential effect of LFA703, pravastatin, and fluvastatin on production of IL-18 and expression of ICAM-1 and CD40 in human monocytes

Hideo Kohka Takahashi, Shuji Mori, Hiromi Iwagaki, Tadashi Yoshino, Noriaki Tanaka, Gabriele Weitz-Schmidt, Masahiro Nishibori

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

A novel, proinflammatory cytokine, interleukin (IL)-18 production was detected in the medium of human monocytes treated with 3-hydroxy-3- methylglutaryl coenzyme-A (HMG-CoA) reductase inhibitors, pravastatin, and fluvastatin (0.1 and 1 μM) but not with the statin-derived lymphocyte function-associated antigen-1 (LFA-1) inhibitor LFA703, which did not inhibit HMG-CoA reductase. Pravastatin and fluvastatin also induced the production of IL-18, tumor necrosis factor a (TNF-α) and interferon-γ (IFN-γ) in human peripheral blood mononuclear cells (PBMC) in contrast to LFA703. BL-18 production by PBMC is located upstream of the cytokine cascade activated by these statins. The IL-18-induced cytokine production was demonstrated to be dependent on adhesion molecule expression on monocytes. In the absence and presence of lower concentrations (0.1 and 1 ng/ml) of IL-18, pravastatin and fluvastatin inhibited the expression of intercellular adhesion molecule (ICAM)-1 and induced the expression of CD40, whereas LFA703 had no effect. In the presence of higher concentrations (5, 10, and 100 ng/ml) of EL-18, pravastatin, fluvastatin, and LFA703 similarly inhibited the expression of ICAM-1 and CD40 as well as the production of IL-12, TNF-α, and IFN-γ in PBMC. The effects of pravastatin and fluvastatin but not LFA703 were abolished by the addition of mevalonate, indicating the involvement of HMG-CoA reductase in the action of pravastatin and fluvastatin. Thus, the effects of LFA703 were distinct from those of pravastatin and fluvastatin in the presence of lower concentrations of IL-18. It was concluded that LFA703 has the inhibitory effect on an IL-18-initiated immune response without any activation on monocytes.

Original languageEnglish
Pages (from-to)400-407
Number of pages8
JournalJournal of Leukocyte Biology
Volume77
Issue number3
DOIs
Publication statusPublished - Mar 2005

Keywords

  • 3-hydroxy-3-methylglutaryl coenzyme-A
  • Human
  • Peripheral blood mononuclear cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology

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