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.

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors with diverse actions. PPARα and PPARγ are expressed in different lymphocyte subpopulations. Recently, we have observed that PPARα 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 PPARα 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-γ, IL-6, and TNF-α despite similar proliferative responses. We also demonstrate higher expression of PPARα 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 PPARα-independent manner. Thus WY14,643, a fibrate, is a profound immunosuppressive agent.

The purpose of this study was to define objective criteria to calculate a tissue segmentation threshoid for shaded surface display {SSD) rendering of the renal arteries with computed tomography angiography. Contrast-enhanced spiral CT scans were obtained through the renal arteries of nine patients. Six sets of SSD images were rendered for each patient with Iower threshold values ranging from 80 to 130 Hounsfield units (HU) by increments of 10 HU. Visceral organ enhancement was measured in the aorta, liver, spleen, pancreas, and kidney. The segmentation threshold for each patient was determined by evaluation of the SSD images alone as well as by comparison with conventional arteriograms. The ideal threshold, as shown by comparison with conventional arteriography, was better correlated with a threshold value selected by qualitative evaluation of SSD images alone (rs = .42}, than with measured enhancement in visceral organs (rs = -.289 to .009). The degree of stenosis was overestimated in a single renal artery (1 of 18) because of an inappropriate threshold selected by evaluation of the SSD images alone. In comparison with a segmentation threshold calculated from measured enhancement of visceral organs, a segmentation threshold selected by qualitative evaluation of the resulting SSD images is more likely to approximate the ideal threshold. Given the subjective nature of such threshold selection, further evaluation is warranted to determine whether threshold selection may result in inaccurate grading of stenosis.