The atypical antipsychotic clozapine selectively inhibits interleukin 8 (IL-8)-induced neutrophil chemotaxis.

Clozapineis the most effective antipsychotic to date, but its benefits are counterbalanced by the risk of severe hematological effects. In this study, we analyzed whether clozapineinhibits polymorphonuclear (PMN) leukocyte chemotaxis. We found that clozapine, within the therapeutic concentration range, potently and selectively inhibits PMN chemotaxisinduced 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, clozapinedid not inhibit PMN chemotaxisby 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 clozapinewith 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, clozapineattenuated 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 chemotaxisinduced by IL-8, but gave conflicting results when tested for its ability to reduce LTB4 release, increasing LTB4 efflux by itself but reducing the