Suppression of nuclear factor-κB and stimulation of inhibitor κB by troglitazone:: Evidence for an antiinflammatory effect and a potential antiatherosclerotic effect in the obese

To elucidate whether troglitazone exerts an antiinflammatory effect in humans, in vivo, we investigated the suppression of nuclear factor kappaB (NF kappaB) in mononuclear cells (MNC) by this drug. We measured intranuclear NF kappaB, total cellular NF kappaB, inhibitor KB (I kappaB)alpha, reactive oxygen species (ROS) generation, and p47(phox) subunit (a key component protein of nicotinamide adenine dinucleotide phosphate oxidase) in MNC. Plasma tumor necrosis factor (TNF)-alpha, soluble intercellular adhesion molecule-1 (sICAM-1), monocyte chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor type 1 (PAI-1), C-reactive protein (CRP), and interleukin (IL)-10 (antiinflammatory cytokine) concentrations were also measured as mediators of inflammatory activity that are regulated by the proinflammatory transcription factor NF kappaB. Seven nondiabetic obese patients were given 400 mg troglitazone daily for 4 weeks. Blood samples were collected before and at weekly intervals thereafter. MNC were separated; and the levels of intranuclear NF kappaB, total cellular NF kappaB, IkappaBalpha, and p47(phox) subunit and ROS generation were determined. Plasma was used to measure insulin glucose, TNF alpha, sICAM, MCP-1, PAI-1, CRP, and IL-10. Plasma insulin concentrations fell significantly at week 1, from 31.2 +/- 29.1 to 14.2 +/-: 11.4 mU/L (P < 0.01) and remained low throughout 4 weeks. Plasma glucose concentrations did not alter significantly. There was a fall in intranuclear NFB, total cellular NF kappaB, and p47(phox) subunit, With an increase in cellular I kappa Ba at week 2, which persisted until week 4. There was a parallel fall in ROS generation by MNC at week 1; this progressed and persisted until week 4 (P < 0.001). Plasma TNF-, sICAM-1, MCP-1, and PAI-1 concentrations fell significantly at week 4. Plasma IL-10 concentration increased significantly, whereas plasma CRP concentrations decreased. We conclude that troglitazone has an antiinflammatory action that may contribute to its putative antiatherosclerotic effects.