EFFECT OF PDE4 INHIBITORS ON ZYMOSAN-INDUCED IL-8 RELEASE FROM HUMAN NEUTROPHILS - SYNERGISM WITH PROSTANOIDS AND SALBUTAMOL

1 The activation of neutrophils with particulate stimuli such as zymos an induces the generation of the C-X-C chemokine interleukin (IL)-8. T here is evidence that neutrophil derived IL-8 plays an important role in human diseases such as the adult respiratory distress syndrome. In the present study, we examined the effects of cyclic AMP elevating age nts on the ability of human neutrophils to generate IL-8 in response t o zymosan particles. 2 The PDE4 inhibitor rolipram had limited effect on zymosan-induced IL-8 generation. In contrast, the PDE4 inhibitors R P 73401 and SE 207499 concentration-dependently suppressed IL-8 genera tion. The potency of these inhibitors was RP 73401 > SB 207499 > rolip ram which is correlated with their rank order of potency at inhibiting the catalytic site of purified neutrophil PDE4. Pretreatment of neutr ophils with the PDE3 inhibitor ORG 9935 or the PDE5 inhibitor zaprinas t had no effect on IL-8 generation. 3 The prostanoids prostaglandin E- 1 (PGE(1)) and PGE(2) inhibited zymosan-induced IL-8 release from neut rophils in a dose-dependent manner. in response to 10(-5) M PGE(1) and PGE(2) inhibiting IL-8 generation by 89% and 75%, respectively. Simil arly, the beta(2)-adrenoceptor agonist salbutamol also inhibited IL-8 generation, but it was less effective than the prostanoids. 4 Signific ant synergism between prostanoids or salbutamol and the PDE4 inhibitor s to inhibit IL-8 generation was observed. In contrast. there was no s ignificant synergism between PGE(2) and the PDE3 inhibitor ORG 9935 or the PDE5 inhibitor zaprinast. 5 In order to evaluate the potential ro le of protein kinase A in mediating the inhibitory effects of cyclic A MP-elevating agents, we used the protein kinase A inhibitors, H 89 and KT 5720. Pretreatment of neutrophils with these drugs completely reve rsed the inhibitory effects of a combination treatment with rolipram a nd PGE(2) on zymosan-induced IL-8 release. 6 Microscopic examination r evealed that most neutrophils contained one or more zymosan particles and that combination treatment with rolipram and PGE(2) noticeably red uced the number of ingested particles. Moreover, there was a significa nt reduction in the percentage of neutrophils which ingested three or more zymosan particles. 7 Thus, our results demonstrate that cyclic AM P-elevating agents modulate the ability of neutrophils to generate IL- 8 in response to a particulate stimulus. However, these agents also mo dulate the ability of neutrophils to phagocytose zymosan particles. Wh ether this effect will translate into inhibition of the ability of neu trophils to deal with infectious agents needs to be investigated furth er.