WY14,643, a PPAR alpha ligand, has profound effects on immune responses in vivo

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors with diverse actions. PPARalpha and PPARgamma are expressed in different lymphocyte subpopulations. Recently, we have observed that PPARalpha 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 PPARalpha 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 (pMOG(35-55)), following immunization with pMOG(35-55)/CFA. Following in vitro restimulation with pMOG(35-55), splenocytes harvested from WY14,643-fed mice demonstrate impaired production of IFN-gamma, IL-6, and TNF-alpha despite similar proliferative responses. We also demonstrate higher expression of PPARalpha 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 PPARalpha-independent manner. Thus WY14,643, a fibrate, is a profound immunosuppressive agent.