l-796449 and 2-4-thiazolidinedione

The effects of L-796,449 (3-chloro-4-(3-(3-phenyl-7-propylbenzofuran-6-yloxy)propylthio)phenylacetic acid; referred to henceforth as compound G), a thiazolidinedione-unrelated peroxisome proliferator activated-receptor-gamma (PPAR-gamma) agonist, on early signaling in lipopolysaccharide-activated RAW 264.7 macrophages were analyzed and compared with those elicited by 15-deoxy-Delta(12,14)-prostaglandin J(2) and the thiazolidinedione rosiglitazone. Compound G inhibited the activation of nuclear factor kappa B through the impairment of the targeting and degradation of I kappa B proteins and promoted a redistribution of I kappa B alpha and I kappa B beta in the nucleus of activated cells. Compound G inhibited I kappa B kinase (IKK) activity both in vivo and in vitro, suggesting a direct mechanism of interaction between this molecule and the IKK complex. The effect of compound G on IKK activity was independent of PPAR-gamma engagement because RAW 264.7 cells expressed negligible levels of this nuclear receptor, and rosiglitazone failed to mimic these actions. Moreover, treatment of activated macrophages with compound G enhanced the synthesis of superoxide anion, which, in combination with the NO produced under activation conditions, triggered apoptosis through the intracellular synthesis of peroxynitrite. These results suggest that compound G might contribute to the resolution of inflammation by favoring the induction of apoptosis through mechanisms independent of PPAR-gamma engagement.

Topics: Anions; Apoptosis; Benzofurans; Blotting, Northern; Blotting, Western; Cell Nucleus; Chloramphenicol O-Acetyltransferase; Cytosol; Dose-Response Relationship, Drug; Flow Cytometry; Genes, Reporter; Glutathione Transferase; I-kappa B Kinase; Immunohistochemistry; Kinetics; Ligands; Macrophage Activation; Macrophages; Microscopy, Confocal; NF-kappa B; Nitric Oxide; Phenylacetates; Plasmids; Protein Serine-Threonine Kinases; Reactive Oxygen Species; Receptors, Cytoplasmic and Nuclear; Recombinant Fusion Proteins; Rosiglitazone; Thiazoles; Thiazolidinediones; Time Factors; Transcription Factors; Transfection