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

Husam Ghanim, Rajesh Garg, Ahmad Aljada, Priya Mohanty, Yuvraj Kumbkarni, Ezzat Assian, Wael Hamouda, Paresh Dandona

Research output: Contribution to journalArticlepeer-review

226 Scopus citations

Abstract

To elucidate whether troglitazone exerts an antiinflammatory effect in humans, in vivo, we investigated the suppression of nuclear factor κB (NFκB) in mononuclear cells (MNC) by this drug. We measured intranuclear NFκB, total cellular NFκB, inhibitor κB (IκB)α, reactive oxygen species (ROS) generation, and p47phox subunit (a key component protein of nicotinamide adenine dinucleotide phosphate oxidase) in MNC. Plasma tumor necrosis factor (TNF)-α 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 NFκB. 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 NFκB, total cellular NFκB, IκBκ, and p47 phox subunit and ROS generation were determined. Plasma was used to measure insulin glucose, TNFα, 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 NFκB, total cellular NFκB, and p47 phox subunit, with an increase in cellular IκBα 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-α 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.

Original languageEnglish (US)
Pages (from-to)1306-1312
Number of pages7
JournalJournal of Clinical Endocrinology and Metabolism
Volume86
Issue number3
DOIs
StatePublished - 2001
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

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