title: Elevated glucose and diabetes promote interleukin-12 cytokine gene expression in mouse macrophages.
abstract: Inflammation is emerging as an important mechanism for micro- and macrovascular complication of diabetes. The macrophage plays a key role in the chronic inflammatory response in part by generating particular cytokines. IL-1beta, IL-6, IL12, IL-18, TNFalpha, and interferon-gamma are produced primarily in macrophages and have been associated with accelerated atherosclerosis and altered vascular wall function. In this study, we evaluated the effect and mechanism of high glucose (HG) on gene expression of these cytokines in mouse peritoneal macrophages (MPM). HG led to a 2-fold increase in the mRNA expression of these cytokines, with IL-12 showing the highest activation (5.4-fold) in a time-dependent (3-12 h) and dose-dependent (10, 17.5, and 25 mmol/liter) manner. The effects were specific to HG because mannitol and 3-O-methyl-glucose had no effect on cytokine mRNA expression. HG also increased IL-12 protein accumulation from MPM. We also explored the role of induced and spontaneous diabetes on inflammatory cytokine expression in MPM. Increases in expression in MPM of multiple inflammatory cytokines, including a 20-fold increase in IL-12 mRNA, were observed in streptozotocin-induced type 1 diabetic mice as well as type 2 diabetic db/db mice, suggesting that cytokine gene expression is increased by hyperglycemia in vivo. We next explored potential mechanisms of HG-induced increases in IL-12 mRNA. HG increased the activity of protein kinase C, p38 MAPK (p38), c-Jun terminal kinase, and inhibitory-kappaB kinase in MPM. Furthermore, inhibitors of these signaling pathways significantly reduced HG-induced IL-12 mRNA expression in MPM. These results provide evidence for a potentially important mechanism linking elevated glucose and diabetes to inflammation.
authors.affiliation: Diabetes and Hormone Center, University of Virginia, Charlottesville, 22908, USA.
authors.forename: Yeshao
authors.initials: Y
authors.lastname: Wen
authors.forename: Jiali
authors.initials: J
authors.lastname: Gu
authors.forename: Shu-Lian
authors.initials: SL
authors.lastname: Li
authors.forename: Marpadga A
authors.initials: MA
authors.lastname: Reddy
authors.forename: Rama
authors.initials: R
authors.lastname: Natarajan
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Nadler
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D051550:I-kappa B Kinase / Q000378:metabolism; D007249:Inflammation; D007375:Interleukin-1 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis / Q000378:metabolism*; D020382:Interleukin-18 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016207:Cytokines; D007375:Interleukin-1; D020382:Interleukin-18; D015850:Interleukin-6; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D051550:I-kappa B Kinase; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D005947:Glucose