The immune modulator FTY720 targets sphingosine-kinase-dependent migration of human monocytes in response to amyloid beta-protein and its precursor.
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.
Kaneider
Nicole C
NC
Division of General Internal Medicine, Department of Internal Medicine, Innsbruck University Hospital, Innsbruck, Austria.
Lindner
Julia
J
Feistritzer
Clemens
C
Sturn
Daniel H
DH
Mosheimer
Birgit A
BA
Djanani
Angela M
AM
Wiedermann
Christian J
CJ
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D016564:Amyloid beta-Protein Precursor / Q000494:pharmacology*; D000730:Androstadienes / Q000494:pharmacology; D001839:Bombesin / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D002772:Cholera Toxin / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000068876:Fingolimod Hydrochloride; D005786:Gene Expression Regulation / Q000187:drug effects; D020962:Heterotrimeric GTP-Binding Proteins / Q000502:physiology; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects*; D008301:Maleimides / Q000494:pharmacology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009479:Neuropeptides / Q000494:pharmacology; D037342:Pertussis Toxin / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000502:physiology*; D011409:Propylene Glycols / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D049349:Receptors, Lysosphingolipid / Q000819:agonists / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D053381:Secretogranin II; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019311:Staurosporine / Q000494:pharmacology; D020032:Tyrphostins / Q000494:pharmacology; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology; D000077191:Wortmannin; D000099157:Sphingosine Kinase
D015056:1-Methyl-3-isobutylxanthine; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000730:Androstadienes; D001839:Bombesin; D015740:Calcitonin Gene-Related Peptide; D002772:Cholera Toxin; D004791:Enzyme Inhibitors; D000068876:Fingolimod Hydrochloride; D020962:Heterotrimeric GTP-Binding Proteins; D007155:Immunologic Factors; D007211:Indoles; D008301:Maleimides; D009240:N-Formylmethionine Leucyl-Phenylalanine; D009479:Neuropeptides; D037342:Pertussis Toxin; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor); D011409:Propylene Glycols; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D049349:Receptors, Lysosphingolipid; D053381:Secretogranin II; D013110:Sphingosine; D019311:Staurosporine; D020032:Tyrphostins; D014660:Vasoactive Intestinal Peptide; D000077191:Wortmannin; D000099157:Sphingosine Kinase; C081159:secretoneurin; C070515:bisindolylmaleimide I; C061800:N,N-dimethylsphingosine; C005682:safingol; C060641:tyrphostin A23