IBUDILAST, AN ANTIALLERGIC 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 mu M) for more than 10 minutes, fMLP- or PMA-induced chemiluminescence was enhanced. However, the fMLP-induced chemiluminescence was suppressed by incubati on for less than 10 minutes. This suppressed effect was missing with P MA-induced chemiluminescence. On the both fMLP- and PMA-induced chemil uminescence, the priming effect of ibudilast was further enhanced by t he 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 tyros ine kinase. Ibudilast showed a transient stimulatory effect on cyclic AMP accumulation which continued for only a few minutes. Ibudilast sho wed no significant effect on phospholipase D dependent chemiluminescen ce, 1,4,5 trisphosphate level, or protein kinase C activity. Ibudilast inhibited extracellular calcium influx. These results suggest that ib udilast acts on or through tyrosine kinase to achieved its priming eff ect on the fMLP-induced chemiluminescence. The early and transient inc rease in cyclic AMP level may explain the inhibitory effect of ibudila st on the fMLP-induced chemiluminescence after short time of incubatio n.