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High glucose induces IL-1 expression in human monocytes: mechanistic insights

Laboratory for Atherosclerosis and Metabolic Research, University of California Davis Medical Center, Sacramento; and Veterans Affairs Medical Center, Mather, California

Submitted 28 December 2006 ; accepted in final form 5 April 2007

Previously, IL-1 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-1 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-1 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-B, and NADPH oxidase were used to determine the mediators in parallel experiments under HG conditions. IL-1-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-1 expression pattern; however, the molar ratio of IL-1 to IL-1RA was increased. Data from inhibitor and small interfering RNA experiments indicate that IL-1 release under HG is mediated by PKC-, via phosphorylation of p38 MAPK, and ERK1/2 leading to NF-B activation, resulting in increased mRNA and protein for IL-1. At the same time, it appears that NADPH oxidase via p47phox activates NF-B, resulting in increased IL-1 secretion. Data suggest that, under HG conditions, monocytes release significantly higher amounts of IL-1 through multiple mechanisms, further compounding the disease progression. Targeting signaling pathways mediating IL-1 release could result in the amelioration of inflammation and possibly diabetic vasculopathies.

protein kinase C; diabetes; p38 phosphorylation; interleukin-1

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