DIFFERENTIAL REGULATION OF EARLY PHASE AND LATE-PHASE RESPONSES IN HUMAN NEUTROPHILS BY CAMP

The elevation of intracellular levels of cyclic AMP by forskolin stimu lation of adenylate cyclase regulates early and late phase neutrophil responses differentially. Early phase neutrophil responses as measured by shape change in response to chemotactic factors, transmigration ac ross a polycarbonate membrane and priming were unaffected by forskolin -induced elevation of intracellular cAMP. Late phase neutrophil respon ses such as release of superoxide anions, activation of phospholipase A2 and platelet activating factor (PAF) synthesis were inhibited by in creasing intracellular cAMP through the addition of 10 muM forskolin f or 10 min prior to stimulation. N-Formyl-methiony-leucylphenylalanine- stimulated arachidonic acid release fell from 9.3% (untreated cells) t o 4.6% in forskolin-treated cells. PAF generation was also inhibited f rom 430 pg/10(6) cells in untreated cells to background levels in fors kolin-treated cells (110 pg/10(6) cells). Also, the reduction of cytoc hrome c by superoxide anions fell from 4.2 nmol/10(6) cells in the abs ence of forskolin to 2.0 nmol/10(6) cells following forskolin treatmen t. These results indicate that in neutrophils the elevation of cAMP ac ts differentially on cellular responses, not affecting early activatio n events, but markedly inhibiting late events such as the release of i nflammatory mediators.