Dieldrin induces human neutrophil superoxide production via protein kinases C and tyrosine kinases

We have recently found that dieldrin is a potent human neutrophil agonist in vitro and induces neutrophilic inflammation in vivo. Among the responses observed in vitro, dieldrin was found to induce superoxide (O2-) production by a yet unknown mechanism. In the present study, dieldrin- and phorbol 12-myristate 13-acetate (PMA)-induced O2- responses were compared. For this purpose, cells were preincubated with a panel of signal transduction inhibitors including genistein, H-7, HA-1077, pertussis toxin, staurosporine, calphostin C, SB203580, PD098059, and wortmannin. Dieldrin-induced O2- response was significantly reduced with treatment with genistein, H-7, HA-1077, staurosporine, and calphostin C, whereas PMA-induced response was significantly reduced by treatment with H-7, HA-1077, and staurosporine. This indicates that dieldrin mediates its effect via protein kinases C (PKCs) and tyrosine kinases. Involvement of tyrosine kinases in dieldrin-induced human neutrophils was further demonstrated by an increase in tyrosine phosphorylated protein level expression. Finally, we found that treatment with the mitochondrial stabilizer bongkrekic acid and with the inhibitor of vesicular transport brefeldin A did not reverse dieldrin-induced O2- response.