title: High glucose induces IL-1beta expression in human monocytes: mechanistic insights.
abstract: Previously, IL-1beta secretion from Type 2 diabetic patients has been shown to be increased compared with controls. In this study, we aimed to delineate the mechanism of IL-1beta induction under high-glucose (HG) conditions in human monocytes. THP-1 cells cultured in normal glucose were treated with increasing concentrations of d-glucose (10-25 mM) for 6-72 h. IL-1beta and IL-1 receptor antagonist levels were measured by ELISA and Western blots, whereas mRNA was quantitated by RT-PCR. Specific inhibitors and small interfering RNAs of PKC, p38, ERK1/2, NF-kappaB, and NADPH oxidase were used to determine the mediators in parallel experiments under HG conditions. IL-1beta-secreted protein, cellular protein, and mRNA increase under HG conditions is time and dose dependent, with maximum increase at 15 mM (48 h; P < 0.05). IL-1 receptor antagonist release was time and dose dependent, similar to IL-1beta expression pattern; however, the molar ratio of IL-1beta to IL-1RA was increased. Data from inhibitor and small interfering RNA experiments indicate that IL-1beta release under HG is mediated by PKC-alpha, via phosphorylation of p38 MAPK, and ERK1/2 leading to NF-kappaB activation, resulting in increased mRNA and protein for IL-1beta. At the same time, it appears that NADPH oxidase via p47phox activates NF-kappaB, resulting in increased IL-1beta secretion. Data suggest that, under HG conditions, monocytes release significantly higher amounts of IL-1beta through multiple mechanisms, further compounding the disease progression. Targeting signaling pathways mediating IL-1beta release could result in the amelioration of inflammation and possibly diabetic vasculopathies.
authors.affiliation: Laboratory for Atherosclerosis and Metabolic Research, University of California Davis Medical Center, 4635 2nd Ave., Research Bldg. 1, Sacramento, CA 95817, USA.
authors.forename: Mohan R
authors.initials: MR
authors.lastname: Dasu
authors.forename: Sridevi
authors.initials: S
authors.lastname: Devaraj
authors.forename: Ishwarlal
authors.initials: I
authors.lastname: Jialal
mesh_terms: D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008954:Models, Biological; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D034741:RNA, Small Interfering / Q000494:pharmacology; D013997:Time Factors
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D016328:NF-kappa B; D034741:RNA, Small Interfering; D011493:Protein Kinase C; D005947:Glucose