vasoactive-intestinal-peptide and sphingosine-kinase

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