Correction: Glucagon-Like Peptide-1(9-36) Inhibits Chemokine-Induced Migration of Human CD4-Positive Lymphocytes

Abstract

Introduction: Inhibitors of dipeptidyl peptidase-IV (DPP-IV), which decrease the degradation of glucose-lowering to the metabolically inactive , are current new treatment options for patients with type 2 diabetes mellitus, a high-risk population for cardiovascular disease. However, the effects of the metabolite GLP-1(9-36) on atherosclerosis are unknown. Thus, the present study examined the effect of GLP-1(9-36) on chemokine-induced CD4-positive lymphocyte migration as one of the early and critical steps in atherogenesis.Methods and Results: Stimulation of isolated human CD4-positive lymphocytes with SDF-1 led to a 3.4 fold (p,0.001; n = 7) increase in cell migration. Pretreatment of cells with GLP-1(9-36) reduced this effect in a concentration-dependent manner by 41% to a 2.0 fold induction at 10 nmol/L GLP-1(9-36) (p,0.001 compared to SDF-1-treated cells, n = 7). Similar effects were obtained when RANTES was used as a chemokine to induce cell migration. The action of GLP-1(9-36) on CD4-positive lymphocyte migration was mediated through an early inhibition of chemokine-induced PI-3 kinase activity. Downstream in the PI-3 kinase signaling pathway, GLP-1(9-36) inhibited SDF-1-induced phosphorylation of MLC and cofilin and decreased factin formation as well as ICAM3 translocation as shown by Western blotting, flow cytometry and immunohistochemistry, respectively. However, the effect of GLP-1(9-36) on PI-3 kinase signaling was not associated with increased intracellular levels of cAMP. Furthermore, experiments with siRNA demonstrated that the inhibitory effect of GLP-1(9-36) on SDF-1induced ICAM3-translocation was preserved in human CD4-positive lymphocytes lacking the GLP-1 receptor, suggesting signaling independent of the known GLP-1 receptor.Conclusion: Thus, GLP-1(9-36) inhibits chemokine-induced CD4-positive lymphocyte migration by inhibition of the PI3kinase pathway independent of cAMP and GLP-1 receptor signaling. Further studies are needed to assess whether such effects may be clinically relevant for patients with type 2 diabetes treated with DPP-IV inhibitors.

Glucagon-Like Peptide-1 Receptor Regulates Macrophage Migration in Monosodium Urate-Induced Peritoneal Inflammation

“…GLP-1 agonists have been increasingly used for the treatment of diabetes in clinical practice because of its insulinotropic beneficial effects against insulin resistance (2). The biological effects of GLP-1 are mediated by glucagon-like peptide-1 receptor (GLP-1R) (3), a seven-transmembrane G protein-coupled receptor family (4) that is expressed on many cell types, including macrophages (5)(6)(7)(8)(9). Translational and clinical studies have shown that GLP-1 and GLP-1R regulate glucose homeostasis and energy metabolism (10) and are involved in important physiological processes such as insulin release, b-cell proliferation, reduced glucagon release, delayed gastric emptying, and enhanced memory (11,12).…”