High glucose induces enhanced expression of resistin in human U937 monocyte-like cell line by MAPK- and NF-kB-dependent mechanisms; the modulating effect of insulin

Abstract

Resistin has emerged as a significant local and systemic regulatory cytokine involved in inflammation. In diabetic patients, the serum resistin level is increased, monocytes/macrophages being an important source of resistin production. We therefore hypothesize that high glucose concentrations (HG) regulate resistin expression in human monocytes. Our aim has been to uncover the potential signalling pathways involved in this process. We have also questioned whether insulin has an effect on the regulation of resistin expression induced by HG. Human monocytes (U937 cell line) were exposed to 25 mM glucose for 24 h and then resistin gene expression and protein levels were determined by reverse transcription with the polymerase chain reaction and Western blot assays. We found that (1) the gene expression and protein level of resistin were up-regulated by HG; (2) the inhibitors of the mitogen-activated protein kinases (MAPKs) p38 (SB203580), extracellular signal-regulated kinases 1/2 (ERK1/2; PD98059) and c-Jun N-terminal kinase (SP600125) and of the transcription factor nuclear factor kappa-B (PDTC) inhibited HG-induced resistin protein production and (3) insulin reduced HG-induced resistin expression via a mechanism independent of phosphatidylinositol 3-kinase (PI3K) or p38 and ERK1/2. Therefore, HG significantly increases resistin gene expression and protein production in the U937 cell line by mechanisms involving MAPKs and the transcription factor NF-kB, whereas insulin reduces its expression. This study adds new data concerning the molecular mechanisms involved in the pro-inflammatory effects of HG on human monocytes.

High Insulin and Leptin Increase Resistin and Inflammatory Cytokine Production from Human Mononuclear Cells

“…High glucose concentrations also upregulated resistin gene expression and protein levels in the human U937 monocytic cell line, an effect mediated by MAPK and NF-kB-dependent mechanisms [33]. In contrast, insulin diminished resistin expression by 30–37% in 3T3-L1 mouse adipocytes acting possibly through the Phosphoinositide (PI)-3, ERK, or p38-MAP- kinases pathways [32, 34].…”

Effects of Psychological Stress on Innate Immunity and Metabolism in Humans: A Systematic Analysis

“…This transition also indicates the condition where cortisol levels start declining and reach basal levels (L1) by time t 1 . It is important to note that excess of glucose levels are known to increase production of pro-inflammatory cytokines [65], [66]. Blood glucose levels might be one of the mechanisms involved in controlling cortisol levels (since excess of cortisol can create a hyperglycemic state).…”

Fibroblast growth factor 1 ameliorates diabetic nephropathy by an anti-inflammatory mechanism

“…In addition to NF-κB, HG can also activate JNK, 41 which is an important player in inflammation and regulates the transcription of a number of inflammatory cytokines. 35,42 We observed that not only HG activated JNK in mesangial cells, podocytes, tubular cells, and macrophages, but renal tissue from T2D and T1D presented with activated JNK as well, and FGF1 prevented JNK activation in each of those cases.…”