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Differential effect of LFA703, pravastatin, and fluvastatin on production of IL‐18 and expression of ICAM‐1 and CD40 in human monocytes
Author(s) -
Takahashi Hideo Kohka,
Mori Shuji,
Iwagaki Hiromi,
Yoshino Tadashi,
Tanaka Noriaki,
WeitzSchmidt Gabriele,
Nishibori Masahiro
Publication year - 2005
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 - 10.1189/jlb.0904510
Subject(s) - pravastatin , fluvastatin , hmg coa reductase , statin , biology , tumor necrosis factor alpha , cytokine , peripheral blood mononuclear cell , proinflammatory cytokine , hydroxymethylglutaryl coa reductase , monocyte , pharmacology , endocrinology , reductase , immunology , inflammation , biochemistry , in vitro , cholesterol , simvastatin , enzyme
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 α (TNF‐α) and interferon‐γ (IFN‐γ) in human peripheral blood mononuclear cells (PBMC) in contrast to LFA703. IL‐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 IL‐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.