title: 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.
authors.affiliation: Institute of Cellular Biology and Pathology N. Simionescu, 8 BP Hasdeu Street, PO Box 35-14, 050568, Bucharest, Romania.
authors.forename: Daniela
authors.initials: D
authors.lastname: Stan
authors.forename: Manuela
authors.initials: M
authors.lastname: Calin
authors.forename: Ileana
authors.initials: I
authors.lastname: Manduteanu
authors.forename: Monica
authors.initials: M
authors.lastname: Pirvulescu
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Gan
authors.forename: Elena Dragomir
authors.initials: ED
authors.lastname: Butoi
authors.forename: Viorel
authors.initials: V
authors.lastname: Simion
authors.forename: Maya
authors.initials: M
authors.lastname: Simionescu
mesh_terms: D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D052243:Resistin / Q000235:genetics / Q000378:metabolism*; D020298:U937 Cells; D015854:Up-Regulation
chemical_list: D005419:Flavonoids; D007093:Imidazoles; D007328:Insulin; D016328:NF-kappa B; D011725:Pyridines; D052243:Resistin; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D005947:Glucose; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one