Inhibition of human neurophil degranulation by forskolin in the presence of phosphodiesterase inhibitors

Abstract

The secretory response of cytochalasin B-treated human polymorphonuclear neutrophils to the peptide chemoattractant f-Met-Leu-Phe (FMLP), the calcium ionophore A23187 and other secretagogues was measured by assaying neutrophil supernatants for the granular enzymes β-glucuronidase and lysozyme. The dose-dependent enzyme secretion in response to 10 −8 -10 −4 M FMLP and A23187 was unaffected by pretreatment with 10–75 μM forskolin (an activator of adenylate cyclase), but inhibited by high concentrations of prostaglandins E 1 and E 2. The phosphodiesterase inhibitors isobutyl-methyl-xanthine (IBMX), papaverine and Ro 20-1724 dose dependently inhibited enzyme secretion from FMLP- or A23187-treated cells, and this effect was augmented in the presence of 50–75 μM forskolin. Similar results for PGE 1, forskolin and forskolin/IBMX combinations were also obtained using leukotriene B 4, platelet activating factor and C5a des-Arg as secretagogues. We conclude that the adenylate cyclase system of human neutrophils is activatable by forskolin, but that the regulatory effects of adenylate cyclase stimulants in these cells are greatly attenuated unless cyclic AMP-phosphodiesterases are inhibited. Thus the phosphodiesterase activity of neutrophils may be of functional importance and is relevant to the modulation of neutrophil activity in inflammation.