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Ligand, Has Profound Effects on Immune Responses In Vivo1
,,,
* Research Service, Veterans Affairs San Diego Healthcare System,
Biomedical Sciences Graduate Program, and Departments of
Cellular and Molecular Medicine and
Medicine, University of California, San Diego, CA 92161
Peroxisome proliferator-activated receptors (PPARs) are
ligand-activated transcription factors with diverse actions. PPAR
and PPAR
are expressed in different lymphocyte subpopulations.
Recently, we have observed that PPAR ligands elicit augmented IL-4
expression in cultures of mitogen-activated splenocytes. The following
studies were undertaken to characterize the in vivo effects of
WY14,643, a PPAR ligand. Our studies demonstrate that oral
administration of WY14,643 markedly reduces splenocyte number in
immunized and nonimmunized C57BL/6 mice. Mice fed WY14,643 display
impaired IgG responses to myelin oligodendrocyte glycoprotein peptide
35–55 (pMOG35–55), following immunization with
pMOG35–55/CFA. Following in vitro restimulation with
pMOG35–55, splenocytes harvested from WY14,643-fed mice
demonstrate impaired production of IFN-, IL-6, and TNF- despite
similar proliferative responses. We also demonstrate higher expression
of PPAR in B than T cells. Finally, to obtain an understanding of
the cause of splenocyte depletion with fibrate therapy, we studied the
effect of WY14,643 on apoptosis of activated splenocytes. WY14,643 in
vitro induces apoptosis in lymphocytes and this effect appears to occur
in a PPAR-independent manner. Thus WY14,643, a fibrate, is a
profound immunosuppressive agent.
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