Peroxisome proliferator-activated receptor-gamma-independent inhibition of macrophage activation by the non-thiazolidinedione agonist L-796,449. Comparison with the effects of 15-deoxy-delta(12,14)-prostaglandin J(2).
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.
Castrillo
A
A
Instituto de Bioquimica, Centro Mixto CSIC-UCM, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain.
Mojena
M
M
Hortelano
S
S
Boscá
L
L
D000838:Anions; D017209:Apoptosis; D001572:Benzofurans / Q000494:pharmacology*; D015152:Blotting, Northern; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D017930:Genes, Reporter; D005982:Glutathione Transferase / Q000378:metabolism; D051550:I-kappa B Kinase; D007150:Immunohistochemistry; D007700:Kinetics; D008024:Ligands; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000378:metabolism*; D018613:Microscopy, Confocal; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010648:Phenylacetates / Q000494:pharmacology*; D010957:Plasmids / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D000077154:Rosiglitazone; D013844:Thiazoles / Q000819:agonists* / Q000494:pharmacology; D045162:Thiazolidinediones; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection
D000838:Anions; D001572:Benzofurans; C436325:L 796449; D008024:Ligands; D016328:NF-kappa B; D010648:Phenylacetates; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; D009569:Nitric Oxide; C089946:2,4-thiazolidinedione; D015500:Chloramphenicol O-Acetyltransferase; D005982:Glutathione Transferase; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase