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A Role for Bid in Eosinophil Apoptosis and in Allergic Airway Reaction¹

Marielle Maret^2,*, Claude Ruffié^2,3,*, Séverine Létuvé^*, Aurélie Phelep^*, Olivier Thibaudeau, Joëlle Marchal^*, Marina Pretolani^* and Anne Druilhe^3,4,*

^* Institut National de la Santé et de la Recherche Médicale Unité 700 and Université Paris Diderot-Paris 7, Paris, France; and Institut National de la Santé et de la Recherche Médicale Institut Fédératif de Recherche 02 and Université Paris Diderot-Paris 7, Paris, France

Bid, a proapoptotic member of Bcl-2 family, is involved in Fas receptor signaling. Fas activation promotes human eosinophil cell death and is believed to accelerate the resolution of pulmonary Th2-driven allergic reaction in mice. We hypothesized that Bid would regulate eosinophil apoptosis and Ag-induced airway inflammation, particularly eosinophilia. C57BL/6 Bid^–/– and wild-type mice were immunized and repeatedly challenged with OVA, and bronchoalveolar lavage (BAL) fluid, lung, and spleen were collected 4–240 h after the final challenge. Cultured BAL eosinophils from Bid-deficient mice showed resistance to Fas-mediated apoptotic DNA fragmentation, phosphatidylserine exposure, mitochondria depolarization, and caspase-3 activity. In addition, OVA-challenged Bid^–/– mice had higher BAL eosinophilia and a lower proportion of BAL apoptotic eosinophils than Bid^+/+ mice. This was accompanied by augmented BAL levels of the eosinophilotactic cytokine, IL-5, and of the eosinophil-associated mediators, TGF-β1 and fibronectin. Finally, cultured OVA-stimulated lung mononuclear cells and splenocytes from Bid-deficient mice showed increased release of the Th2-type cytokines, IL-4 and IL-5, but no change in cell number. We conclude that Bid modulates BAL eosinophilia by regulating both eosinophil apoptosis and Th2-type cytokine production.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Inserm and by the Grant No. 0012405 from the ‘Agence Nationale de la Recherche’.

² M.M. and C.R. equally contributed to this work.

³ Current address: Laboratoire Génomique virale et vaccination, Institut Pasteur, Paris, France (C.R.); and Centre de Recherche Institut National de la Santé et de la Recherche Médicale U845, Equipe "Mécanismes et stratégies thérapeutiques des néphropathies chroniques" and Université Paris Descartes, Paris, France (A.D.).

⁴ Address correspondence and reprint requests to Dr. Anne Druilhe, Centre de Recherche INSERM U845, Equipe ‘Mécanismes et stratégies thérapeutiques des néphropathies chroniques’, 6^ième étage Tour Lavoisier, Hôpital Necker-Enfants Malades, 149 Rue de Sèvres, Paris, France. E-mail address: anne.druilhe{at}inserm.fr

⁵ Abbreviations used in this paper: EPO, eosinophil peroxidase; WT, wild type; BAL, bronchoalveolar lavage; PI, propidium iodide; DioC₆(3), 3,3'-dihexyloxacarbocyanine; DEVDfmk, aspartate glutamate valine aspartate fluoromethylketone.

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