Glucagon-like peptide-1(9-36) inhibits chemokine-induced migration of human CD4-positive lymphocytes

• Published in: PloS one Vol. 8; no. 3; p. e58445
• Main Authors: Liberman, Ana, Esser, Melanie, Marx, Nikolaus, Burgmaier, Mathias
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 04.03.2013; Public Library of Science (PLoS)
• Subjects: 1-Phosphatidylinositol 3-kinase; Actin; Actin Depolymerizing Factors - genetics; Actin Depolymerizing Factors - metabolism; Actins - genetics; Actins - metabolism; Antigens, CD - genetics; Antigens, CD - metabolism; Arteriosclerosis; Atherogenesis; Atherosclerosis; Biology; Cardiology; Cardiomyopathy; Cardiovascular diseases; CD4 antigen; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - metabolism; Cell adhesion & migration; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; Cell migration; Cells, Cultured; Chemokine CCL5 - pharmacology; Chemokine CXCL12 - pharmacology; Chemokines; Chemotaxis - drug effects; Cofilin; Complications and side effects; Cyclic AMP; Cyclic AMP - metabolism; Cytometry; Development and progression; Diabetes; Diabetes mellitus; Dipeptidyl-peptidase IV; Dipeptidyl-Peptidase IV Inhibitors - pharmacology; Dose-Response Relationship, Drug; Flow cytometry; Gastrointestinal hormones; Gene expression; Gene Expression Regulation - drug effects; Genetic aspects; Glucagon; Glucagon-like peptide 1; Glucagon-Like Peptide 1 - analogs & derivatives; Glucagon-Like Peptide 1 - pharmacology; Glucagon-Like Peptide-1 Receptor; Health aspects; Health risks; Humans; Immune response; Immunohistochemistry; Inhibition; Inhibitors; Internal medicine; Intracellular levels; Intracellular signalling; Kinases; Leukocyte migration; Lymphocyte Activation - drug effects; Lymphocytes; Medicine; Patients; Peptidase; Peptides; Peptides - pharmacology; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Pretreatment; Protein Transport - drug effects; RANTES; Receptors, Glucagon - antagonists & inhibitors; Receptors, Glucagon - genetics; Receptors, Glucagon - metabolism; RNA, Small Interfering - genetics; SDF-1 protein; Signal transduction; Signal Transduction - drug effects; Studies; Translocation; Type 2 diabetes; Western blotting; Aachen Germany; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0058445

Inhibitors of dipeptidyl peptidase-IV (DPP-IV), which decrease the degradation of glucose-lowering GLP-1(7-36) to the metabolically inactive GLP-1(9-36), 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. 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 f-actin 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-1-induced ICAM3-translocation was preserved in human CD4-positive lymphocytes lacking the GLP-1 receptor, suggesting signaling independent of the known GLP-1 receptor. Thus, GLP-1(9-36) inhibits chemokine-induced CD4-positive lymphocyte migration by inhibition of the PI3-kinase 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.