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Cutting Edge: Prostaglandin D₂ Enhances Leukotriene C₄ Synthesis by Eosinophils during Allergic Inflammation: Synergistic In Vivo Role of Endogenous Eotaxin¹

Fabio P. Mesquita-Santos^*, Adriana Vieira-de-Abreu^*, Andrea S. Calheiros^*, Isabela H. Figueiredo^*, Hugo C. Castro-Faria-Neto^*, Peter F. Weller, Patrícia T. Bozza^*, Bruno L. Diaz and Christianne Bandeira-Melo^2,*

^* Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Rio de Janeiro, Brazil; Department of Medicine, Harvard Medical School, Boston, MA 02215; and Divisão de Biologia Celular, Instituto Nacional do Cncer, Rio de Janeiro, Brazil

In addition to the well-recognized ability of prostaglandin D₂ (PGD₂) to regulate eosinophil trafficking, we asked whether PGD₂ was also able to activate eosinophils and control their leukotriene C₄ (LTC₄)-synthesizing machinery. PGD₂ administration to presensitized mice enhanced in vivo LTC₄ production and formation of eosinophil lipid bodies–potential LTC₄-synthesizing organelles. Immunolocalization of newly formed LTC₄ demonstrated that eosinophil lipid bodies were the sites of LTC₄ synthesis during PGD₂-induced eosinophilic inflammation. Pretreatment with HQL-79, an inhibitor of PGD synthase, abolished LTC₄ synthesis and eosinophil lipid body formation triggered by allergic challenge. Although PGD₂ was able to directly activate eosinophils in vitro, in vivo PGD₂-induced lipid body-driven LTC₄ synthesis within eosinophils was dependent on the synergistic activity of endogenous eotaxin acting via CCR3. Our findings, that PGD₂ activated eosinophils and enhanced LTC₄ synthesis in vivo in addition to the established PGD₂ roles in eosinophil recruitment, heighten the interest in PGD₂ as a target for antiallergic therapies.