In view of the fact that insulin resistance is associated with atherogenesis and that troglitazone, an insulin sensitizer, has anti-inflammatory effects, which may be potentially antiatherogenic in the long term, we have now investigated whether insulin has potential anti-inflammatory effects. We infused 2.0 to 2.5 IU/h in 5% dextrose (100 mL/h) iv into 10 obese subjects for 4 h followed by 5% dextrose alone for 2 h. The rate of insulin infusion was varied to maintain glucose concentrations as close to the baseline as possible. Blood samples were obtained before and at 2, 4, and 6 h. Subjects were also infused with 5% dextrose without insulin and with saline on separate occasions. Intranuclear nuclear factor kappaB (NFkappaB) in mononuclear cells fell at 2 and further at 4 h, reverting toward the baseline at 6 h (P < 0.05). IkappaB increased significantly at 2 h, increasing further at 4 h and remaining elevated at 6 h (P < 0.001). Reactive oxygen species (ROS) generation by mononuclear cells fell significantly at 2 h and fell further at 4 h; it partially reverted to baseline at 6 h (P < 0.005). p47(phox) subunit, the key protein of nicotinamide adenine dinucleotide phosphate oxidase also fell at 2 h and 4 h, reverting toward the baseline at 6 h (P < 0.05). In addition, soluble intercellular adhesion molecule-1 (sICAM-1), monocyte chemoattractant protein-1 (MCP-1), and plasminogen activator inhibitor-1 (PAI-1) fell significantly following insulin infusion. Glucose or saline infusions without insulin caused no alteration in NFkappaB, IkappaB, ROS generation, p47(phox) subunit, sICAM-1, MCP-1, or PAI-1. We conclude that insulin has a potent acute anti-inflammatory effect including a reduction in intranuclear NFkappaB, an increase in IkappaB, and decreases in ROS generation, p47(phox) subunit, plasma soluble intercellular adhesion molecule-1 (sICAM-1), monocyte chemoattractant protein-1 (MCP-1), and plasminogen activator inhibitor-1 (PAI-1. This acute anti-inflammatory effect, if demonstrated in the long term, may have implications for atherosclerosis and its complications.

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Fibroblast growth factor-binding protein (FGF-BP) is a secreted protein that binds and activates fibroblast growth factors (FGF-1 and FGF-2) and induces angiogenesis in some human cancers. FGF-BP is expressed at high levels in squamous cell carcinoma (SCC) cell lines and tumor samples and has been shown to be rate-limiting for the growth of SCC tumors in vivo. In this study, we examine the regulation of FGF-BP by epidermal growth factor (EGF) and the signal transduction mechanisms that mediate this effect. We found that EGF treatment of the ME-180 SCC cell line caused a rapid induction of FGF-BP gene expression. This induction was mediated transcriptionally through the AP-1 (c-Fos/JunD) and CCAAT/enhancer-binding protein elements as well as through an E-box repressor site in the proximal regulatory region of the FGF-BP promoter. Pharmacological inhibition of protein kinase C and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 (MEK1/2) completely blocked EGF induction of FGF-BP mRNA, whereas inhibition of phosphatidylinositol 3-kinase had no effect. Additionally, both EGF- and anisomycin-induced FGF-BP mRNA was abrogated by inhibition of p38 mitogen-activated protein kinase, demonstrating a role for p38 in the regulation of FGF-BP. Co-transfection of the FGF-BP promoter with dominant negative forms of MEK2, extracellular signal-regulated kinase 2, and p38 significantly decreased the level of EGF induction, whereas expression of a dominant negative c-Jun N-terminal kinase mutant or expression of c-Jun N-terminal kinase inhibitory protein had no effect. Similarly, activation of the p38 pathway by overexpression of wild-type p38 or MKK6 enhanced FGF-BP transcription. These results demonstrate that EGF induction of FGF-BP occurs selectively through dual activation of the stress-activated p38 and the MEK/extracellular signal-regulated kinase mitogen-activated protein kinase pathways, which ultimately leads to activation of the promoter through AP-1 and CCAAT/enhancer-binding protein sites.