Ghanim H, Garg R, Aljada A, Mohanty P, Kumbkarni Y, Assian E, Hamouda W, Dandona P
Division of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo, and Kaleida Health, Buffalo, New York 14209, USA.
J Clin Endocrinol Metab. 2001 Mar;86(3):1306-12. doi: 10.1210/jcem.86.3.7309.
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.
为了阐明曲格列酮在人体内是否具有抗炎作用，我们在体内研究了该药物对单核细胞（MNC）中核因子κB（NFκB）的抑制作用。我们测量了MNC中细胞核内NFκB、细胞总NFκB、抑制因子κB（IkappaB）α、活性氧（ROS）生成以及p47（phox）亚基（烟酰胺腺嘌呤二核苷酸磷酸氧化酶的关键组成蛋白）。还测量了血浆肿瘤坏死因子（TNF）-α、可溶性细胞间黏附分子-1（sICAM-1）、单核细胞趋化蛋白-1（MCP-1）、纤溶酶原激活物抑制剂1型（PAI-1）、C反应蛋白（CRP）以及白细胞介素（IL）-10（抗炎细胞因子）的浓度，这些都是由促炎转录因子NFκB调节的炎症活动介质。7名非糖尿病肥胖患者每天服用400mg曲格列酮，持续4周。在服药前及服药后每周采集血样。分离出MNC，测定细胞核内NFκB、细胞总NFκB、IkappaBα和p47（phox）亚基的水平以及ROS生成。用血浆测量胰岛素、葡萄糖、TNFα、sICAM、MCP-1、PAI-1、CRP和IL-10。血浆胰岛素浓度在第1周显著下降，从31.2±29.1降至14.2±11.4mU/L（P<0.01），并在4周内一直保持较低水平。血浆葡萄糖浓度无显著变化。在第2周，细胞核内NFκB、细胞总NFκB和p47（phox）亚基下降，细胞内IkappaBα增加，并持续到第4周。在第1周，MNC产生的ROS也出现类似下降；这种下降持续进展并一直持续到第4周（P<0.001）。血浆TNF-α、sICAM-1、MCP-1和PAI-1浓度在第4周显著下降。血浆IL-10浓度显著增加，而血浆CRP浓度下降。我们得出结论，曲格列酮具有抗炎作用，这可能有助于其假定的抗动脉粥样硬化作用。
