Details

Autor(en) / Beteiligte

• Schlezinger, Jennifer J
• Jensen, Brenda A
• Mann, Koren K
• Ryu, Heui-Young
• Sherr, David H

Titel

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

Ist Teil von

• The Journal of immunology (1950), 2002-12, Vol.169 (12), p.6831-6841

Ort / Verlag

Am Assoc Immnol

Erscheinungsjahr

2002

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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.