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-Mediated NF-
B Activation and Apoptosis in Pre-B Cells1
* Department of Environmental Health, Boston University School of Public Health, Boston, MA 02118; and
Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec, Canada
The role of peroxisome proliferator-activated receptor 
(PPAR) in adipocyte physiology has been exploited for the treatment
of diabetes. The expression of PPAR 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
agonists, little is known about the consequences of PPAR activation
in the developing immune system. Here, well-characterized models of B
lymphopoiesis were used to investigate the effects of PPAR 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 agonists (ciglitazone and GW347845X)
resulted in rapid apoptosis. A role for PPAR and its dimerization
partner, retinoid X receptor (RXR)
, in death signaling was supported
by 1) the expression of RXR mRNA and cytosolic
PPAR protein, 2) agonist-induced binding of PPAR to a PPRE, and
3) synergistic increases in apoptosis following cotreatment with
PPAR agonists and 9-cis-retinoic acid, an RXR
agonist. PPAR agonists activated NF-
B (p50, Rel A, c-Rel) binding
to the upstream B regulatory element site of c-myc.
Only doses of agonists that induced apoptosis stimulated NF-B-DNA
binding. Cotreatment with 9-cis-retinoic acid and
PPAR agonists decreased the dose required to activate NF-B. These
data suggest that activation of PPAR-RXR initiates a potent
apoptotic signaling cascade in B cells, potentially through NF-B
activation. These results have implications for the nominal role of the
PPAR in B cell development and for the use of PPAR agonists as
immunomodulatory therapeutics.
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