Suppression of nuclear factor-kappaB and stimulation of inhibitor kappaB by troglitazone: evidence for an anti-inflammatory 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 (NFkappaB) in mononuclear cells (MNC) by this drug. We measured intranuclear NFkappaB, total cellular NFkappaB, inhibitor kappaB (IkappaB)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 NFkappaB. 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 NFkappaB, total cellular NFkappaB, IkappaBalpha, and p47 (phox) subunit and ROS generation were determined. Plasma was used to measure insulin glucose, TNFalpha, 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 NFkappaB, total cellular NFkappaB, and p47 (phox) subunit, with an increase in cellular IkappaBalpha 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-alpha, 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.
Ghanim
H
H
Division of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo, and Kaleida Health, Buffalo, New York 14209, USA.
Garg
R
R
Aljada
A
A
Mohanty
P
P
Kumbkarni
Y
Y
Assian
E
E
Hamouda
W
W
Dandona
P
P
D000328:Adult; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001161:Arteriosclerosis / Q000517:prevention & control*; D001786:Blood Glucose / Q000032:analysis; D002097:C-Reactive Protein / Q000032:analysis; D002467:Cell Nucleus / Q000737:chemistry; D018932:Chemokine CCL2 / Q000097:blood; D002839:Chromans / Q000494:pharmacology*; D005260:Female; D006801:Humans; D020672:I-kappa B Proteins / Q000097:blood / Q000502:physiology*; D007328:Insulin / Q000097:blood; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D008875:Middle Aged; D019255:NADPH Oxidases; D016328:NF-kappa B / Q000032:analysis / Q000037:antagonists & inhibitors*; D009765:Obesity / Q000097:blood* / Q000150:complications; D010750:Phosphoproteins / Q000097:blood; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D017382:Reactive Oxygen Species / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D000077288:Troglitazone; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D000893:Anti-Inflammatory Agents; D001786:Blood Glucose; D018932:Chemokine CCL2; D002839:Chromans; D020672:I-kappa B Proteins; D007328:Insulin; D016328:NF-kappa B; D010750:Phosphoproteins; D017395:Plasminogen Activator Inhibitor 1; D017382:Reactive Oxygen Species; D013844:Thiazoles; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D016753:Interleukin-10; D002097:C-Reactive Protein; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D000077288:Troglitazone