vasoactive-intestinal-peptide and safingol

Accumulation of inflammatory mononuclear phagocytes in Alzheimer's senile plaques, a hallmark of the innate immune response to beta-amyloid fibrils, can initiate and propagate neurodegeneration characteristic of Alzheimer's disease. Phagocytes migrate toward amyloid beta-protein involving formyl peptide receptor like-1-dependent signaling. Using human peripheral blood monocytes in Boyden chamber micropore filter assays, we show that the amyloid beta-protein- and amyloid beta-precursor protein-induced migration was abrogated by dimethylsphingosine, a sphingosine kinase inhibitor. Amyloid beta-protein stimulated in monocytes the gene expression for sphingosine-1-phosphate receptors 2 and 5, but not 1, 3, and 4. FTY720 that acts as a sphingosine-1-phosphate receptor agonist after endogenous phosphorylation by sphingosine kinase, as well as various neuropeptides that are known to be monocyte chemoattractants, dose-dependently inhibited amyloid beta-protein-induced migration. These data demonstrate that the migratory effects of beta-amyloid in human monocytes involve spingosine-1-phosphate signaling. Whereas endogenous neuropeptides may arrest and activate monocytes at sites of high beta-amyloid concentrations, interference with the amyloid beta-protein-dependent sphingosine-1-phosphate pathway in monocytes by FTY720, a novel immunomodulatory drug, suggests that FTY720 may be efficacious in beta-amyloid-related inflammatory diseases.

Topics: 1-Methyl-3-isobutylxanthine; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Androstadienes; Bombesin; Calcitonin Gene-Related Peptide; Cell Movement; Chemotaxis, Leukocyte; Cholera Toxin; Drug Evaluation, Preclinical; Enzyme Inhibitors; Fingolimod Hydrochloride; Gene Expression Regulation; Heterotrimeric GTP-Binding Proteins; Humans; Immunologic Factors; Indoles; Leukocytes, Mononuclear; Maleimides; N-Formylmethionine Leucyl-Phenylalanine; Neuropeptides; Pertussis Toxin; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Propylene Glycols; Protein Kinase Inhibitors; Protein Processing, Post-Translational; Receptors, Lysosphingolipid; RNA, Messenger; Secretogranin II; Sphingosine; Staurosporine; Tyrphostins; Vasoactive Intestinal Peptide; Wortmannin

Vasoactive intestinal peptide (VIP) primed the respiratory burst of human neutrophils induced by phorbol myristate acetate (PMA) and by the chemotactic peptide N-formyl-Met-Leu-Phe (fMLP). The sigmoidal-shaped curve of the priming effect of VIP differs for both agonist since the Hill coefficient was close to three in the case of neutrophil activation by fMLP whereas the corresponding value for PMA was close to one. The priming effect of VIP was enhanced when neutrophils were stimulated by FMLP in the presence of sphinganine, a protein kinase C inhibitor, at concentrations which almost abolished the response to PMA. VIP failed to increase resting cytosolic free calcium and to modify the transient increase in [Ca2+]i induced by fMLP. The described results point out that the mechanism of the priming of neutrophils by VIP is also independent of calcium and protein kinase C. The absence of VIP receptors in plasma membrane of neutrophils suggests that a receptor-independent mechanism modulates the agonist-triggered signaling pathway. The priming of neutrophils by VIP can not be considered as a pharmacological effect, as may be deduced from the required VIP concentration; it should be rather considered that the enhancement of the formation of reactive oxygen metabolites by VIP may be interesting in the understanding of the neuroimmune axis.

Topics: Calcimycin; Humans; In Vitro Techniques; N-Formylmethionine Leucyl-Phenylalanine; NADH, NADPH Oxidoreductases; NADPH Oxidases; Neutrophil Activation; Neutrophils; Receptors, Vasoactive Intestinal Peptide; Respiratory Burst; Somatostatin; Sphingosine; Tetradecanoylphorbol Acetate; Vasoactive Intestinal Peptide