title: Inhibition of tumor-necrosis-factor-alpha induced endothelial cell activation by a new class of PPAR-gamma agonists. An in vitro study showing receptor-independent effects.
abstract: Proinflammatory cytokines and adhesion molecules expressed by endothelial cells (ECs) play a critical role in initiating and promoting atherosclerosis. Agents that oppose these inflammatory effects in vascular cells include peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands, including 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2) and synthetic thiazolidinediones. Recently, a new structural class of potent PPAR-gamma agonists, 1,1-bis(3'-indolyl)-1-(p-substituted phenyl) methanes, has been characterized. The purpose of this study was to evaluate the anti-inflammatory effects of two PPAR-gamma-active members of this class, 1,1-bis(3'-indolyl)-1-(p-t-butylphenyl)methane (DIM-C-pPhtBu) and 1,1-bis(3'-indolyl)-1-(p-biphenyl)methane (DIM-C-pPhC(6)H(5)), in ECs in vitro. Pretreatment of ECs with DIM-C-pPhC(6)H(5), DIM-C- pPhtBu, or 15d-PGJ2 decreased tumor necrosis factor-alpha (TNF-alpha)-induced intercellular adhesion molecule (ICAM)-1 expression in a concentration-dependent manner. At a concentration of 10 microM, DIM-C-pPhtBu and DIM-C-pPhC(6)H(5) decreased ICAM-1 expression by 77.5 and 71.3%, respectively, and comparable inhibition (84.4%) was observed for 10 microM 15d-PGJ2 (p < 0.05). In contrast, 10 microM ciglitazone and DIM-C-pPhCH(3), which exhibits low PPAR-gamma agonist activity, were inactive. The two new PPAR-gamma agonists and 15d-PGJ2 also inhibited TNF-alpha-induced interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) production in supernatants of TNF-alpha-stimulated ECs, whereas ciglitazone and DIM-C-pPhCH(3) did not decrease TNF-alpha-induced expression of these two proteins. This new structural class of PPAR-gamma agonists inhibited the expression of ICAM-1 and the production of IL-6 and MCP-1 in TNF-alpha-activated ECs at lower concentrations than other synthetic PPAR-gamma agonists, suggesting the potential clinical utility of 1,1-bis(3'-indolyl)-1-(p-substituted phenyl) methanes for decreasing endothelial inflammation.
authors.affiliation: Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas-Houston Health Science Center, Houston, Tex., USA.
authors.forename: Paolo
authors.initials: P
authors.lastname: Calabrò
authors.forename: Ismael
authors.initials: I
authors.lastname: Samudio
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Safe
authors.forename: James T
authors.initials: JT
authors.lastname: Willerson
authors.forename: Edward T H
authors.initials: ET
authors.lastname: Yeh
mesh_terms: D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects; D047495:PPAR gamma / Q000819:agonists*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D014471:Umbilical Veins / Q000166:cytology; D000093242:Interleukin-6 Inhibitors
chemical_list: D018932:Chemokine CCL2; D007211:Indoles; D018799:Intercellular Adhesion Molecule-1; D047495:PPAR gamma; D015230:Prostaglandin D2; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C505817:1,1-bis(3'-indolyl)-1-(4-biphenyl)methane; C505816:1,1-bis(3'-indolyl)-1-(4-t-butylphenyl)methane; C477819:15-deoxyprostaglandin J2; C111835:CCL2 protein, human