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

Abstract

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 Ͻ 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␤

Variation in Gene Expression of Inflammatory Cytokines in Leukocyte-Derived Cells of High-Fat-Diet-Induced Insulin-Resistant Rats

“…10,[25][26][27] Furthermore, recent cell studies have revealed that monocyte attachment with the vascular endothelial cells and the dysfunction of phagocytosis in neutrophils under the condition of hyperglycemia and hyperinsulinemia were associated with cytokine production in their cells. [14][15][16][17][18][19] However, it has not been determined whether insulin resistance can induce cytokine gene expression in leukocytes in animal models.…”

“…Several cell studies have indicated that the elevation of IL-1 expression in monocyte cell lines by a high glucose and TNF-treatment was associated with attachment of the cells with the HUVEC vascular endothelial cell line. [14][15][16][17] Cell studies have indicated that the induction of IL-1 and TNF-expression in neutrophils by hyperglycemia and hyperinsulinemia was associated with the dysfunction of phagocytosis in the cells. 18,19) Indeed, it is well known that monocyte/macrophage attachment to vascular endothelial cells and adipose tissues, and the dysfunction of phagocytosis in neutrophils can be found in patients and animals with diabetes.…”

Evidence of Increased Inflammation and Microcirculatory Abnormalities in Patients With Type 1 Diabetes and Their Role in Microvascular Complications

“…In addition, p38MAPK activity is increased in diabetic nephropathy. We have previously shown that high glucose activates monocyte IL-1␤ via upregulation of p38MAPK and NF-B activity in vitro (38). In addition, Aljada et al (39) have shown that glucose activates mononuclear NF-B activity.…”

The global diabetes epidemic as a consequence of lifestyle-induced low-grade inflammation

“…One straightforward mechanistic explanation is that there is more substrate for mitochondrial activity as a consequence of increased glucose influx, and that increased respiratory activity gives rise to enhanced release of superoxide anions [6]. However, other studies suggest that glucose-induced superoxide formation stems from glucose-6-phosphate dehydrogenase and phosphokinase C-dependent activation of NAD(P)H oxidase [7]. Subsequently, the production of pro-inflammatory immune mediators occurs via the activation of mitogen-activated kinases p38 and Jun N-terminal kinase (JNK), other tyrosine kinases, transcription factors such as transcription factor activator protein-1 (AP-1) and nuclear factor κB (NFκB), and/or poly(ADPribose) polymerase [8,9].…”