Present address: Departamento de Farmacologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Avenida Antonio Carlos 6627, Belo Horizonte, MG, Brazil - 31270.901.
Effect of PDE4 inhibitors on zymosan-induced IL-8 release from human neutrophils: synergism with prostanoids and salbutamol
Article first published online: 10 FEB 2009
1998 British Pharmacological Society
British Journal of Pharmacology
Volume 123, Issue 6, pages 1260–1266, March 1998
How to Cite
Au, B.-. T., Teixeira, M. M., Collins, P. D. and Williams, T. J. (1998), Effect of PDE4 inhibitors on zymosan-induced IL-8 release from human neutrophils: synergism with prostanoids and salbutamol. British Journal of Pharmacology, 123: 1260–1266. doi: 10.1038/sj.bjp.0701723
- Issue published online: 10 FEB 2009
- Article first published online: 10 FEB 2009
- (Received June 27, 1997, Revised November 18, 1997, Accepted December 8, 1997)
- PDE4 inhibitors;
- cyclic AMP/PKA pathway;
- 1The activation of neutrophils with particulate stimuli such as zymosan induces the generation of the C-X-C chemokine interleukin (IL)-8. There 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 agents on the ability of human neutrophils to generate IL-8 in response to zymosan particles.
- 2The PDE4 inhibitor rolipram had limited effect on zymosan-induced IL-8 generation. In contrast, the PDE4 inhibitors RP 73401 and SB 207499 concentration-dependently suppressed IL-8 generation. The potency of these inhibitors was RP 73401 > SB 207499 > rolipram which is correlated with their rank order of potency at inhibiting the catalytic site of purified neutrophil PDE4. Pretreatment of neutrophils with the PDE3 inhibitor ORG 9935 or the PDE5 inhibitor zaprinast had no effect on IL-8 generation.
- 3The prostanoids prostaglandin E1 (PGE1) and PGE2 inhibited zymosan-induced IL-8 release from neutrophils in a dose-dependent manner, in response to 10−5M PGE1 and PGE2 inhibiting IL-8 generation by 89% and 75%, respectively. Similarly, the β2-adrenoceptor agonist salbutamol also inhibited IL-8 generation, but it was less effective than the prostanoids.
- 4Significant synergism between prostanoids or salbutamol and the PDE4 inhibitors to inhibit IL-8 generation was observed. In contrast, there was no significant synergism between PGE2 and the PDE3 inhibitor ORG 9935 or the PDE5 inhibitor zaprinast.
- 5In order to evaluate the potential role of protein kinase A in mediating the inhibitory effects of cyclic AMP-elevating agents, we used the protein kinase A inhibitors, H 89 and KT 5720. Pretreatment of neutrophils with these drugs completely reversed the inhibitory effects of a combination treatment with rolipram and PGE2 on zymosan-induced IL-8 release.
- 6Microscopic examination revealed that most neutrophils contained one or more zymosan particles and that combination treatment with rolipram and PGE2 noticeably reduced the number of ingested particles. Moreover, there was a significant reduction in the percentage of neutrophils which ingested three or more zymosan particles.
- 7Thus, our results demonstrate that cyclic AMP-elevating agents modulate the ability of neutrophils to generate IL-8 in response to a particulate stimulus. However, these agents also modulate the ability of neutrophils to phagocytose zymosan particles. Whether this effect will translate into inhibition of the ability of neutrophils to deal with infectious agents needs to be investigated further.
British Journal of Pharmacology (1998) 123, 1260–1266; doi:10.1038/sj.bjp.0701723