Sphingomyelinase dependent apoptosis of dendritic cells following treatment with amyloid peptides.
Amyloid peptides are formed during inflammation and modify the function of immune cells. The present study explored the effect of amyloid beta-peptide (Abeta(1-42)) and islet amyloid polypeptide (IAPP) on bone marrow derived dendritic cells (DCs). DCs were treated with Abeta(1-42) or IAPP with subsequent assessment of ceramide formation, caspase 8 and 3 activity, DNA fragmentation and phosphatidylserine exposure. In addition, TNFalpha secretion was assessed in lypopolysaccharide (LPS)-stimulated Abeta(1-42)- or IAPP-treated DCs. Within 24h Abeta(1-42) and IAPP triggered ceramide formation, caspase 8 and caspase 3 activation, DNA fragmentation and annexin V binding in DCs obtained from wild type mice, whereas in DCs from sphingomyelinase deficient (asm(-/-)) mice and in wild type DCs treated with sphingomyelinase inhibitor amitriptyline all these effects were strongly impaired. Moreover, ceramide formation was also reduced in wild type DCs in which acid sphingomyelinase (Asm) was silenced with Asm-targeted siRNA. Finally, Abeta(1-42) and IAPP treatment was further followed by a decline of TNFalpha formation in wild type DCs. In conclusion, amyloid peptides induce DC apoptosis presumably through activation of acid sphingomyelinase resulting in production of ceramide.
Xuan
Nguyen Thi
NT
Department of Physiology, University of Tübingen, Gmelinstr. 5, D-72076 Tübingen, Germany.
Shumilina
Ekaterina
E
Kempe
Daniela S
DS
Gulbins
Erich
E
Lang
Florian
F
D000682:Amyloid / Q000494:pharmacology*; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D001853:Bone Marrow; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D058228:Islet Amyloid Polypeptide; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D013108:Sphingomyelin Phosphodiesterase / Q000172:deficiency / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000682:Amyloid; D016229:Amyloid beta-Peptides; D017304:Annexin A5; D058228:Islet Amyloid Polypeptide; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; C075222:amyloid beta-protein (1-42); D013108:Sphingomyelin Phosphodiesterase; D053148:Caspase 3; D053181:Caspase 8