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Stem Cell Factor-Induced Leukotriene B₄ Production Cooperates with Eotaxin to Mediate the Recruitment of Eosinophils During Allergic Pleurisy in Mice¹

André Klein^2,*, André Talvani^*, Patrícia M. R. Silva, Marco A. Martins, Tim N. C. Wells, Amanda Proudfoot, Nick W. Luckacs and Mauro M. Teixeira^3,*

^* Immunopharmacology, Departamento de Bioquímica e Imunologia, Instituto Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Departmento de Fisiologia e Farmacodinâmica, Instituto Oswaldo Cruz, Fundaçao Oswaldo Cruz, Rio de Janeiro, Brazil; Serono Pharmaceuticals, Geneva, Switzerland; and Department of Pathology, University of Michigan, Ann Arbor, MI 48109

The understanding of the mechanisms underlying eosinophil recruitment in vivo may aid in the development of novel strategies for the treatment of allergic disorders. In this study, we investigated the role of chemokines in the cascade of events leading to eosinophil recruitment in a stem cell factor (SCF)- and leukotriene B₄ (LTB₄)-dependent allergic pleurisy model in mice. The intrapleural administration of the eosinophil-active chemokines eotaxin, RANTES, and macrophage-inflammatory protein 1 (MIP-1) induced a time- and dose-dependent eosinophil recruitment. Pretreatment with anti-eotaxin, but not anti-RANTES or anti-MIP-1, blocked the recruitment of eosinophils following Ag challenge of sensitized animals, and significant eotaxin immunoreactivity was detected in the pleural cavity of these animals. Similarly, only the anti-eotaxin inhibited the eosinophil recruitment induced by injection of SCF in naive animals. However, blockade of SCF did not inhibit the release of eotaxin after Ag challenge of sensitized mice. Akin to its effects on SCF and in the allergic reaction, eotaxin-induced eosinophil recruitment was blocked by the LTB₄ receptor antagonist CP105696. Nevertheless, SCF, but not eotaxin, appeared to regulate the endogenous release of LTB₄ after Ag challenge. Finally, we show that low doses of eotaxin synergized with LTB₄ to induce eosinophil recruitment in the pleural cavity. Overall, the present results show that eotaxin and SCF-induced LTB₄ cooperate to induce eosinophil recruitment into sites of allergic inflammation. Cooperation between inflammatory mediators must be an important phenomenon in vivo, explaining both the ability of lower concentrations of mediators to induce a full-blown functional response and the effectiveness of different strategies at inhibiting these responses.

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