ABSTRACT
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.
Subject(s)
Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/metabolism , Peroxisome Proliferators/administration & dosage , Peroxisome Proliferators/metabolism , Peroxisomes/metabolism , Pyrimidines/administration & dosage , Pyrimidines/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Transcription Factors/metabolism , Administration, Oral , Animals , Antibody Formation/drug effects , Apoptosis/drug effects , Apoptosis/immunology , B-Lymphocyte Subsets/cytology , B-Lymphocyte Subsets/drug effects , B-Lymphocyte Subsets/immunology , B-Lymphocyte Subsets/metabolism , Cell Death/drug effects , Cell Death/immunology , Cytokines/antagonists & inhibitors , Cytokines/biosynthesis , Glycoproteins/administration & dosage , Glycoproteins/immunology , Growth Inhibitors/administration & dosage , Ligands , Lymphocyte Count , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Myelin-Oligodendrocyte Glycoprotein , Peptide Fragments/administration & dosage , Peptide Fragments/immunology , Receptors, Cytoplasmic and Nuclear/biosynthesis , Receptors, Cytoplasmic and Nuclear/deficiency , Receptors, Cytoplasmic and Nuclear/genetics , Spleen/cytology , Spleen/drug effects , Spleen/pathology , T-Lymphocyte Subsets/drug effects , T-Lymphocyte Subsets/pathology , Transcription Factors/biosynthesis , Transcription Factors/deficiency , Transcription Factors/geneticsABSTRACT
Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors with diverse actions including adipocyte differentiation and lipid metabolism. Recent studies have revealed anti-inflammatory activities, but the majority of these studies have been performed in monocyte/macrophages. In these studies, we investigate the effects of PPAR ligands in murine mitogen-activated splenocytes. Ciglitazone, a PPARgamma ligand, consistently decreased IFN-gamma and IL-2 production by mitogen-activated splenocytes and had modest effects on splenocyte proliferation. The effects of WY14,643, a representative of the fibrate class of PPARalpha ligands, on splenocyte proliferation and IL-2 levels are less marked than those observed with the PPARgamma ligand. In addition, treatment with WY14,643 and other fibrates led to marked increases in supernatant concentrations of IL-4. However, treatment with a potent and specific PPARalpha ligand (GW7,647) did not augment IL-4. Also, WY14,643 induced IL-4 expression in splenocytes from PPARalpha knockout mice, suggesting that the fibrate effect on IL-4 was largely through a PPARalpha-independent mechanism. This increase in IL-4 was associated with and causatively related to augmented expression of CD23 by CD45R/B220(+) cells. We also demonstrate that PPARgamma gene expression is up-regulated in T cells by mitogen activation, that it is positively regulated by IL-4 and WY14,643, and that it is blocked by anti-IL-4. Finally, we demonstrate that WY14,643 can modestly augment IL-4 promoter activity in a PPARalpha-independent manner. In concert, these findings support the roles of PPAR ligands in modulating inflammatory responses involving lymphocytes but also establish potent effects of the fibrate class of PPARalpha ligands on IL-4 expression that are receptor independent.
