PROTEIN-KINASE C-INDEPENDENT ACTIVATION OF RAF-1 AND MITOGEN-ACTIVATED PROTEIN-KINASE BY LEUKOTRIENE B-4 IN GUINEA-PIG EOSINOPHILS

Leukotriene B-4 (LTB(4)) and phorbol 12-myristate 13-acetate (PMA) wer e found to activate serine/threonine kinase c-Raf-1 (Raf-1) and mitoge n-activated protein (MAP) kinase in guinea pig eosinophils. Raf-1 was activated by both compounds in a time- and dose-dependent fashion, and the activation by each paralleled that of MAP kinase. The LTB(4) rece ptor antagonist ONO-4057 prevented the LTB(4)-induced activation of Ra f-1 and MAP kinase, but had no effect on the PMA-induced activation of these kinases. The protein kinase C (PKC) inhibitors, (+/-)1-0-hexade cyl-2-0-methylglycerol (AMG-C-16) and bisindolylmaleimide (GF 109203X) , suppressed the PMA-induced activation of Raf-1 and MAP kinase, but n ot the LTB(4)-induced activation of both kinases. Our findings suggest that the activation of Raf-1 and MAP kinase by LTB(4) involves a PKC- independent pathway. (C) 1995 Academic Press,Inc.