Peroxisome Proliferator-Activated Receptor γ-Mediated NF-κB Activation and Apoptosis in Pre-B Cells

Abstract

The role of peroxisome proliferator-activated receptor γ (PPARγ) in adipocyte physiology has been exploited for the treatment of diabetes. The expression of PPARγ 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 PPARγ agonists, little is known about the consequences of PPARγ activation in the developing immune system. Here, well-characterized models of B lymphopoiesis were used to investigate the effects of PPARγ 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 PPARγ agonists (ciglitazone and GW347845X) resulted in rapid apoptosis. A role for PPARγ and its dimerization partner, retinoid X receptor (RXR)α, in death signaling was supported by 1) the expression of RXRα mRNA and cytosolic PPARγ protein, 2) agonist-induced binding of PPARγ to a PPRE, and 3) synergistic increases in apoptosis following cotreatment with PPARγ agonists and 9-cis-retinoic acid, an RXRα agonist. PPARγ agonists activated NF-κB (p50, Rel A, c-Rel) binding to the upstream κB regulatory element site of c-myc. Only doses of agonists that induced apoptosis stimulated NF-κB-DNA binding. Cotreatment with 9-cis-retinoic acid and PPARγ agonists decreased the dose required to activate NF-κB. These data suggest that activation of PPARγ-RXR initiates a potent apoptotic signaling cascade in B cells, potentially through NF-κB activation. These results have implications for the nominal role of the PPARγ in B cell development and for the use of PPARγ agonists as immunomodulatory therapeutics.