Studies on the mechanism of inhibition of chemotactic tripeptide stimulated human neutrophil polymorphonuclear leucocyte superoxide production by chloroquine and hydroxychloroquine.

Abstract

SUMMARYThe effect of chloroquine and hydroxychloroquine on neutrophil superoxide release stimulated by the chemotactic tripeptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) was examined. Both drugs caused time and dose dependent inhibition of superoxide release but had no effect on equilibrium binding of [3H]FMLP to its receptor. Preliminary experiments suggest that these drugs may exert their inhibitory effect on superoxide release by inhibiting the FMLP stimulated hydrolysis of phosphoinositides.Chloroquine (CQ), hydroxychloroquine (HCQ), and previously mepacrine have been widely used in the treatment of rheumatoid arthritis and systemic lupus erythematosus.1 They have both immunosuppressive and anti-inflammatory effects,' 2 which may be mediated by inhibition of polymorphonuclear (PMN) and mononuclear phagocyte function. 1 3 4 Both these cell types are intimately involved in the pathogenesis of inflammatory arthritis.Inhibitory effects of these drugs on phagocyte function have been attributed to their lysosomotropism, which results in inhibition of lysosomal functions, including lysosomal enzyme release, receptor recycling, lysosomal digestion, and metabolism of lipids.1 They also inhibit non-lysosomal functions, including cytokine release2 and chemotaxis.3 We have recently reported that these drugs have differential effects on other non-lysosomal aspects of blood monocyte metabolism and function, including superoxide production, phospholipid methylation, and arachidonic acid (AA) release.4 We have extended these studies to examine the effect of CQ and HCQ on PMN superoxide release stimulated by the chemotactic tripeptide, N-formyl-methionylleucyl-phenylalanine (FMLP).We report here that these agents inhibit FMLP stimulated superoxide release without affecting

Effect of H1-antagonist Dithiaden® on human PMN-leukocyte aggregation and chemiluminescence is stimulus-dependent

“…The divergent effect of Dit on fMLP-stimulated CL requires further investigation. Similar biphasic effects have been described for several cationic amphiphilic drugs (CAD) on superoxide anion production from stimulated PMNL [15,20]. Moreover, Dit together with His showed pronounced antagonism on CL induced at receptor (fMLP) stimulation.…”

“…In blood platelets, Dit like other CAD, inhibited dose-dependently the liberation of arachidonic acid from membrane phospholipids stimulated at different levels and inhibited thromboxane generation through stimulated human PMNL [11,26]. Another CAD, chloroquine, suppressed the generation of ROS and decreased the arachidonic acid liberation from membrane phospholipids of human PMNL [15,19].…”

Selective inhibition of extracellular oxidants liberated from human neutrophils—A new mechanism potentially involved in the anti-inflammatory activity of hydroxychloroquine

“…Since PKCβII participates directly in the activation of neutrophil NADPH oxidase on the plasma membrane [4], its inhibition may be involved in reduced extracellular chemiluminescence of neutrophils treated with hydroxychloroquine. In contrast to the assumption of Hurst et al [22], hydroxychloroquine did not diminish the intracellular chemiluminescence and did not affect proteins which regulate the formation of oxidants inside neutrophils. Neither phosphorylation of p40 phox (an enzyme component allowing the assembly of NADPH oxidase on intracellular membranes [48]), nor phosphorylation of PKCδ (the isoform of protein kinase C which controls the directing of cytosolic oxidase components to intracellular membranes [4]), was inhibited in the presence of this drug.…”

“…Nevertheless, neutrophils and neutrophil-derived oxidants participate substantially in the mechanisms that drive the onset of chronic inflammation-by inducing tissue damage and by modulating activities of other immune cells [11,20,21]. Under in vitro conditions, the effect of hydroxychloroquine on superoxide anion liberation was studied by Hurst et al [22,23]. Since these authors assumed an interference with NADPH oxidase in specific granules of neutrophils, we analysed effects of hydroxychloroquine separately on extra-and intracellular formation of oxidants as well as on the phosphorylation of p40 phox , an oxidase component essential for intracellular ROS formation.…”

Antiplatelet and Antileukocyte Effects of Cardiovascular,Immunomodulatory and Chemotherapeutic Drugs

“…Both, CQ and hydroxychloroquine inhibited the response of human PMNL to superoxide [373]. CQ could either inhibit or enhance 5-lipoxygenase product synthesis in human PMNL, depending on the stimulus used and inhibited the naphthol AS-D chloroacetate esterase in isolated PMNL but had no effect on -naphthyl acetate esterase and -naphthyl butyrate esterase [350,374].…”