Increased secretion of IP-10 from monocytes under hyperglycemia is via the TLR2 and TLR4 pathway

被引:37
|
作者
Devaraj, Sridevi [1 ]
Jialal, Ishwarlal [1 ,2 ]
机构
[1] UC Davis Med Ctr, Dept Med Pathol & Lab Med, Lab Atherosclerosis & Metab Res, Robert E Stowell Endowed Chair Expt Pathol, Sacramento, CA 95817 USA
[2] Vet Affairs Med Ctr, Mather, CA USA
关键词
Chemokine; IP-10; Macrophage; Toll like receptors; Transcription; TOLL-LIKE RECEPTORS; PROLIFERATIVE DIABETIC-RETINOPATHY; MICROVASCULAR COMPLICATIONS; CXC CHEMOKINES; KAPPA-B; TYPE-1; EXPRESSION; CELLS; ATHEROSCLEROSIS; INFLAMMATION;
D O I
10.1016/j.cyto.2009.02.004
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Among the chemokines, members of the CXC family include IP-10 (interferon-gamma induced protein of 10 kDa). Elevated serum IP-10 levels have been shown in diabetes. However, there is a paucity of data examining the sources and regulation of IP-10 under hyperglycemic conditions and this was the overall aim of the study. Type I diabetes (T1DM) is a pro-inflammatory state. We previously demonstrated increased toll like receptor (TLR) 2 and 4 activation in monocytes of T1DM patients. Thus, we also examined the role of the TLR pathway in modulating IP-10 release from human monocytes under hyperglycemia. Also, circulating and monocytic levels of IP-10 in patients with T1DM with and without microvascular complications (T1DM-MV and T1DM) and controls (C) was assessed. Under HG, IP-10 mRNA and protein were significantly increased compared to normoglycemia. Incubation of monocytes with dominant negative Ikb but not control vector significantly abrogated HG-induced IP-10 release. Furthermore, both TLR2 siRNA as well as TLR4 siRNA, either alone or in combination significantly abrogated HG-induced IP-10 release. Serum and monocytic levels of IP-10 were significantly increased in T1DM and T1DM-MV compared to matched controls. Thus, we demonstrate increased circulating and monocytic IP-10 in T1DM. Down-regulation of TLR2 and TLR4 abrogates HG-induced IP-10 release via NF-kappa B inhibition. (C) 2009 Elsevier Ltd. All rights reserved.
引用
收藏
页码:6 / 10
页数:5
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