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The Journal of Immunology, 2002, 169: 6831-6841.
Copyright © 2002 by The American Association of Immunologists

Peroxisome Proliferator-Activated Receptor {gamma}-Mediated NF-{kappa}B Activation and Apoptosis in Pre-B Cells1

Jennifer J. Schlezinger2,*, Brenda A. Jensen*, Koren K. Mann{dagger}, Heui-Young Ryu* and David H. Sherr*

* Department of Environmental Health, Boston University School of Public Health, Boston, MA 02118; and {dagger} Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec, Canada

The role of peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) in adipocyte physiology has been exploited for the treatment of diabetes. The expression of PPAR{gamma} in lymphoid organs and its modulation of macrophage inflammatory responses, T cell proliferation and cytokine production, and B cell proliferation also implicate it in immune regulation. Despite significant human exposure to PPAR{gamma} agonists, little is known about the consequences of PPAR{gamma} activation in the developing immune system. Here, well-characterized models of B lymphopoiesis were used to investigate the effects of PPAR{gamma} ligands on nontransformed pro/pre-B (BU-11) and transformed immature B (WEHI-231) cell development. Treatment of BU-11, WEHI-231, or primary bone marrow B cells with PPAR{gamma} agonists (ciglitazone and GW347845X) resulted in rapid apoptosis. A role for PPAR{gamma} and its dimerization partner, retinoid X receptor (RXR){alpha}, in death signaling was supported by 1) the expression of RXR{alpha} mRNA and cytosolic PPAR{gamma} protein, 2) agonist-induced binding of PPAR{gamma} to a PPRE, and 3) synergistic increases in apoptosis following cotreatment with PPAR{gamma} agonists and 9-cis-retinoic acid, an RXR{alpha} agonist. PPAR{gamma} agonists activated NF-{kappa}B (p50, Rel A, c-Rel) binding to the upstream {kappa}B regulatory element site of c-myc. Only doses of agonists that induced apoptosis stimulated NF-{kappa}B-DNA binding. Cotreatment with 9-cis-retinoic acid and PPAR{gamma} agonists decreased the dose required to activate NF-{kappa}B. These data suggest that activation of PPAR{gamma}-RXR initiates a potent apoptotic signaling cascade in B cells, potentially through NF-{kappa}B activation. These results have implications for the nominal role of the PPAR{gamma} in B cell development and for the use of PPAR{gamma} agonists as immunomodulatory therapeutics.




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