induction of apoptosis in mouse t cells upon peroxisome proliferator-activated receptor gamma (ppar-γ) binding

Abstract

Peroxisome proliferator-activated receptors (PPARs) are a family of ligand-activated nuclear receptor transcription factors. PPARs heterodimerize with the retinoic acid X receptor upon ligand binding. This complex then binds to PPAR responsive elements (PPREs) located in the promoter regions of various genes and acts to regulate their expression (Westin, et al., 1998). Although there are several PPARs, much attention has recently focused on PPAR-γ. Two isoforms of PPAR-γ have been found in mice - PPARγl and PPAR-γ2. PPAR-γ2 is found exclusively in adipose tissue and regulates adipogenesis. PPAR-γl, however, is expressed at low levels in many cells such as smooth muscle cells, macrophages, and epithelial cells (Ma, et al., 1998). Ligand binding of PPAR-γl has many functions including inhibition of migration of vascular smooth muscle cells, inhibition of inducible nitric oxide synthase in murine macrophages, and apoptosis of some colonic tumor cell lines (Kitamura, et al., 1999, Spiegelman, et al., 1997, Vedin, et al., 1996). Metabolites of prostaglandin D2 (PGD₂) have been suggested to be natural ligands for PPAR-γ. For example, 15-deoxy-Δ^12,14-PGJ₂(herein referred to as 15-d-PGJ₂) as well as other prostaglandins of the J series can bind and activate PPARγin vitro.Synthetic ligands for PPAR-yhave also been identified, and include the thiazoldinediones (i.e. ciglitazone, troglitazone) (Schoonjans, et al., 1997, Willson, et al., 1996). These compounds are anti-hyperglycemic drugs currently used to treat non-insulin dependent diabetes.