Ibudilast, an anti-allergic and cerebral vasodilator, modulates superoxide production in human neutrophils.
We evaluated the effect of ibudilast on superoxide generation in human neutrophils by chemiluminescence development using luciferine analog, FCLA. By incubating neutrophils with ibudilast (2-200 microM) for more than 10 minutes, fMLP- or PMA-induced chemiluminescence was enhanced. However, the fMLP-induced chemiluminescence was suppressed by incubation for less than 10 minutes. This suppressed effect was missing with PMA-induced chemiluminescence. On the both fMLP- and PMA-induced chemiluminescence, the priming effect of ibudilast was further enhanced by the treatment with H-7, a protein kinase C inhibitor. In contrast, the priming effect of ibudilast on the fMLP-induced chemiluminescence was abolished by the treatment with ST-638, a selective inhibitor of tyrosine kinase. Ibudilast showed a transient stimulatory effect on cyclic AMP accumulation which continued for only a few minutes. Ibudilast showed no significant effect on phospholipase D dependent chemiluminescence, 1,4,5 trisphosphate level, or protein kinase C activity. Ibudilast inhibited extracellular calcium influx. These results suggest that ibudilast acts on or through tyrosine kinase to achieved its priming effect on the fMLP-induced chemiluminescence. The early and transient increase in cyclic AMP level may explain the inhibitory effect of ibudilast on the fMLP-induced chemiluminescence after short time of incubation.
Niwa
M
M
Department of Pharmacology, Gifu University School of Medicine, Japan.
Kohno
K
K
al-Essa
L Y
LY
Kobayashi
M
M
Nozaki
M
M
Tsurumi
K
K
D002118:Calcium / Q000097:blood; D000242:Cyclic AMP / Q000097:blood; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000097:blood; D008163:Luminescent Measurements; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D013481:Superoxides / Q000097:blood*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*; D007212:Indolizines; D011720:Pyrazoles
D002118:Calcium; D000242:Cyclic AMP; D015544:Inositol 1,4,5-Trisphosphate; D009240:N-Formylmethionine Leucyl-Phenylalanine; D011725:Pyridines; D013481:Superoxides; D013755:Tetradecanoylphorbol Acetate; D014665:Vasodilator Agents; C038366:ibudilast; D007212:Indolizines; D011720:Pyrazoles