Cytotoxic enzyme release and oxygen centered radical formation in human neutrophils are selectively inhibited by E-type prostaglandins but not by PGI2

Abstract

The action of PGE1, PGE2, PGI2 and iloprost on superoxide anion generation, lysosomal enzyme release, and changes of Ca2+ fluxes in human polymorphonuclear leukocytes (PMN) was studied in vitro. Both PGE-type compounds were equipotent inhibitors of FMLP-and PAF-stimulated superoxide anion generation, beta-glucuronidase release (IC50 3-5 mumol/l) and Ca2+ influx while PGI2 and iloprost were ineffective at concentrations up to 10 mumol/l. These inhibitory actions of PGE1 and PGE2 were paralleled by an increase in cAMP level of the PMN while no change occurred with PGI2 and iloprost. None of the prostaglandins affected the initial intracellular Ca2+ liberation after challenge with FMLP or PAF. Preincubation of PMN with PGE1 and PGE2 but not with iloprost resulted in subsequent desensitization against a second administration of these compounds. None of the compounds affected PMN activation produced by arachidonic acid or calcimycin (A 23187). These data demonstrate that PGE-type compounds are effective inhibitors of receptor-mediated (PAF, FMLP) activation of human PMN while prostacyclins are considerably less potent. This suggests that the inhibitory prostaglandin receptor on human PMN belongs to the E-type being functionally different from the inhibitory prostaglandin receptor on human platelets. These results suggest that compounds, such as PGE1 and PGE2 might be superior to prostacyclins to prevent PMN-associated generation of reactive oxygen species and lysosomal enzyme release in situations with endogenous PMN activation, i.e. inflammatory reactions.

Contribution of capsaicin-sensitive sensory neurons to stress-induced increases in gastric tissue levels of prostaglandins in rats

“…Gastric tissue levels of 6-keto-PGF 1␣ , a stable metabolite of PGI 2 , and PGE 2 were increased 30 min after WIR, which contributed to prevent the WIR-induced gastric mucosal injury mainly by inhibiting neutrophil activation (9,12,13,18). However, the mechanisms underlying the increase in the gastric tissue level of PGI 2 and PGE 2 have not been fully clarified.…”

“…Hecker et al (18) demonstrated that, although PGE 2 inhibited N-formyl-methionyl-leucyl-phenylalanine-induced cytotoxic enzyme release from human neutrophils by increasing intracellular levels of cAMP, neither PGI 2 nor iloprost, a stable analog of PGI 2 , had any effect. In contrast, Kainoh et al (22) reported that both PGE 2 and PGI 2 inhibited oxygen free radical production by increasing intracellular cAMP levels in rat polymorphonuclear leukocytes.…”

Characterization of the PGE receptor subtype mediating inhibition of superoxide production in human neutrophils

“…The exact mechanism by which cyclic AMP inhibits O2-generation still remains to be elucidated. However, it has been demonstrated (Hecker et al, 1989;Ney & Schror, 1991) that the increase in intracellular cyclic AMP produced by PGE2 in human neutrophils is paralleled by a decrease in extracellular Ca2+ influx which may lead to the attenuation of receptor-mediated neutrophil activation by FMLP. It is interesting to note that Sedgwick et al (1985) found that although cyclic AMP levels increased in all neutrophils stimulated by the three different neutrophil activators, FMLP, phorbol myristate acetate and serum-treated zymosan, inhibition of 02-was seen only in the neutrophils treated with FMLP.…”

Investigation of the inhibitory effects of PGE2 and selective EP agonists on chemotaxis of human neutrophils

“…Human neutrophil activation is inhibited by prostaglandin E2 (PGE2) (Wong & Freund, 1980;Hecker et al, 1989) and PGD2 (Ney & Schror, 1991) and this has been linked to the ability of these compounds to activate adenylate cyclase. It has previously been shown that inhibition of N-formyl-methionylleucine-phenylalanine (FMLP)-induced superoxide generation by PGE2 is mediated by the occupation of EP2 receptors and activation of adenylate cyclase, leading to the elevation of intracellular levels of adenosine 3':5'-cyclic monophosphate (cyclic AMP) (Talpain et al, 1995).…”