title: The atypical antipsychotic clozapine selectively inhibits interleukin 8 (IL-8)-induced neutrophil chemotaxis.
abstract: Clozapine is the most effective antipsychotic to date, but its benefits are counterbalanced by the risk of severe hematological effects. In this study, we analyzed whether clozapine inhibits polymorphonuclear (PMN) leukocyte chemotaxis. We found that clozapine, within the therapeutic concentration range, potently and selectively inhibits PMN chemotaxis induced by interleukin 8 (IL-8), a chemokine inducing neutrophil migration. The effect was not due to its action at dopamine, serotonin and muscarinic receptors, or to a direct antagonism to IL-8 receptors. Furthermore, clozapine did not inhibit PMN chemotaxis by its presumed toxic mechanism. In fact, after an overnight incubation in cell culture, the drug did not increase the physiological PMN apoptosis. An interference of clozapine with the autocrine release of leukotriene B4 (LTB4), a secondary chemoattractant secreted by neutrophils in response to the primary chemoattractant IL-8, was hypothesized. In agreement with this hypothesis, clozapine attenuated the IL-8-induced release of LTB4 in PMNs. A series of experiments with an antagonist of the LTB4 receptor, U75302, and an inhibitor of LTB4 synthesis, zileuton, provided support to this conjecture. Intriguingly MK-571, an inhibitor of the multi-drug resistance protein MRP4, playing a pivotal role in effluxing LTB4, completely blocked PMN chemotaxis induced by IL-8, but gave conflicting results when tested for its ability to reduce LTB4 release, increasing LTB4 efflux by itself but reducing the release when in combination with IL-8. The reduction of PMN chemotaxis due to clozapine could predispose patients to infections. Whether this effect is a prelude to clozapine agranulocytosis requires further investigation.
authors.affiliation: Biotechnological and Applied Clinical Sciences Department, University of L׳Aquila, 67100 L׳Aquila, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Capannolo
authors.affiliation: Biotechnological and Applied Clinical Sciences Department, University of L׳Aquila, 67100 L׳Aquila, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Fasciani
authors.affiliation: Biotechnological and Applied Clinical Sciences Department, University of L׳Aquila, 67100 L׳Aquila, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Romeo
authors.affiliation: Biotechnological and Applied Clinical Sciences Department, University of L׳Aquila, 67100 L׳Aquila, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Aloisi
authors.affiliation: Molecular Signaling Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Rossi
authors.affiliation: Biotechnological and Applied Clinical Sciences Department, University of L׳Aquila, 67100 L׳Aquila, Italy.
authors.forename: Pierangelo
authors.initials: P
authors.lastname: Bellio
authors.affiliation: Biotechnological and Applied Clinical Sciences Department, University of L׳Aquila, 67100 L׳Aquila, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Celenza
authors.affiliation: Department of Life, Health and Environment Sciences, University of L׳Aquila, 67100 L׳Aquila, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Cinque
authors.affiliation: Department of Life, Health and Environment Sciences, University of L׳Aquila, 67100 L׳Aquila, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Cifone
authors.affiliation: Department of Translational Research and New Technology in Medicine, University of Pisa, 56126 Pisa, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Scarselli
authors.affiliation: Biotechnological and Applied Clinical Sciences Department, University of L׳Aquila, 67100 L׳Aquila, Italy. Electronic address: roberto.maggio@univaq.it.
authors.forename: Roberto
authors.initials: R
authors.lastname: Maggio
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002460:Cell Line; D002633:Chemotaxis / Q000187:drug effects*; D003024:Clozapine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005233:Fatty Alcohols / Q000494:pharmacology; D005434:Flow Cytometry; D006018:Glycols / Q000494:pharmacology; D006801:Humans; D020287:In Situ Nick-End Labeling; D016209:Interleukin-8 / Q000494:pharmacology*; D020024:Leukotriene Antagonists / Q000494:pharmacology; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D009504:Neutrophils / Q000187:drug effects*; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D023062:Receptors, Interleukin-8A / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D014150:Antipsychotic Agents; D005233:Fatty Alcohols; D006018:Glycols; D016209:Interleukin-8; D020024:Leukotriene Antagonists; D011422:Propionates; D011804:Quinolines; D023062:Receptors, Interleukin-8A; C062137:U 75302; D007975:Leukotriene B4; C059141:verlukast; D000262:Adenylyl Cyclases; D003024:Clozapine
keywords: Agranulocytosis; Clozapine; Leukotriene B4; Multi-drug resistance proteins; Neutrophil chemotaxis