title: Increased secretion of IP-10 from monocytes under hyperglycemia is via the TLR2 and TLR4 pathway.
abstract: Among the chemokines, members of the CXC family include IP-10 (interferon-gamma induced protein of 10kDa). 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 1 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-kappaB inhibition.
authors.affiliation: Department of Medical Pathology and Laboratory Medicine, Laboratory for Atherosclerosis and Metabolic Research, Robert E.Stowell Endowed Chair in Experimental Pathology, UC Davis Medical Center, Sacramento, CA 95817, USA.
authors.forename: Sridevi
authors.initials: S
authors.lastname: Devaraj
authors.forename: Ishwarlal
authors.initials: I
authors.lastname: Jialal
mesh_terms: D000293:Adolescent; D000328:Adult; D054357:Chemokine CXCL10 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000378:metabolism*; D051550:I-kappa B Kinase / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D051195:Toll-Like Receptor 2 / Q000235:genetics*; D051197:Toll-Like Receptor 4 / Q000235:genetics*; D014162:Transfection; D055815:Young Adult
chemical_list: C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D008070:Lipopolysaccharides; D016328:NF-kappa B; D034741:RNA, Small Interfering; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051550:I-kappa B Kinase; D005947:Glucose