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

Abstract

IntroductionInhibitors 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.Methods and ResultsStimulation 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.ConclusionThus, 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.

Metabolically-inactive glucagon-like peptide-1(9–36)amide confers selective protective actions against post-myocardial infarction remodelling

“…Nonetheless, taken together with the observation that MI-induced macrophage infiltration was almost completely prevented by GLP-1(9–36), these data strongly suggest that this purportedly inactive peptide exerts significant actions which are relevant to cardiac remodelling. Whilst these findings are consistent with a previous report of GLP-1(9–36)-mediated inhibition of chemokine-induced migration of human CD4-positive lymphocytes [ 44 ], which is established as an early and critical step in atherogenesis, ours is the first study to specifically link an immunomodulatory effect of GLP-1(9–36) to cardioprotection. Although this apparent modulation of the myocardial inflammatory response by GLP-1(9–36) is most likely to impact upon ECM remodelling and thereby explain the observed preservation of cardiac function, it is also possible that reduced cardiac macrophage infiltration and associated changes in gene expression may also influence cardiomyocyte function due to modulation of established paracrine communication between these two cell populations [ 45 ].…”

Immunological alterations with GLP‐1 agonists in people living with HIV

“…In summary, our preliminary data suggest a potential effect of GLP-1 RA treatment on circulating CD4 T-cells in people living with HIV in a non-time-dependent manner. Our findings are in line with previous findings in DPP-4 inhibitors [2] as well as experimental findings of potential interactions of GLP-1 with T-lymphocytes [3,4]. The true effect of GLP-1 RAs might have been diluted due to a shortage of GLP-1 RAs during recent months, potentially leading to involuntary pauses before the routine blood withdrawals that might not have been fully captured due to the retrospective study design.…”

GLP-1: benefits beyond pancreas

“…Furthermore, their sequence seems to be homologous to these sequences of the family of G protein receptors for several other endocrine peptides such as glucagon, secretin, calcitonin, GHRH, PTH and vasoactive intestinal peptide [1]. Some evidence, in particular in myocardium, osteoblasts and lymphocytes models, also suggests that extra-pancreatic effects of GLP-1 could be mediated by receptors other than the ''classical'' GLP-1 receptor [24][25][26]. Furthermore, the GLP-1 (9-36), which is classically considered as an insulinotropic-inactive metabolite, shares some of the cardiac effects of the ''active'' GLP-1 (7-36), at least in rodents [25].…”