Anti-inflammatory effects of phosphatidylcholine.
We recently showed that mucus from patients with ulcerative colitis, a chronic inflammatory disorder of the colon, is characterized by a low level of phosphatidylcholine (PC) while clinical studies reveal that therapeutic addition of PC using slow release preparations is beneficial. The positive role of PC in this disease is still elusive. Here we tested the hypothesis that exogenous application of PC has anti-inflammatory properties using three model systems. First, human Caco-2 cells were treated with tumor necrosis factor-alpha (TNF-alpha) to induce a pro-inflammatory response via activation of NF-kappaB. Second, latex bead phagosomes were analyzed for their ability to assemble actin in vitro, a process linked to pro-inflammatory signaling and correlating with the growth versus killing of mycobacteria in macrophages. The third system used was the rapid assembly of plasma membrane actin in macrophages in response to sphingosine 1-phosphate. TNF-alpha induced a pro-inflammatory response in Caco-2 cells, including 1) assembly of plasma membrane actin; 2) activation of both MAPKs ERK and p38; 3) transport of NF-kappaB subunits to the nucleus; and 4) subsequent up-regulation of the synthesis of pro-inflammatory gene products. Exogenous addition of most PCs tested significantly inhibited these processes. Other phospholipids like sphingomyelin or phosphatidylethanolamine showed no effects in these assays. PC also inhibited latex bead phagosome actin assembly, the killing of Mycobacterium tuberculosis in macrophages, and the sphingosine 1-phosphate-induced actin assembly in macrophages. TNF-alpha induces the activation of signaling molecules and the reorganization of the actin cytoskeleton in human intestinal cells. Exogenous application of PC blocks pro-inflammatory signaling in Caco-2 cells, in phagosomes in vitro and facilitates intracellular survival of mycobacteria. We provide further evidence that actin assembly by membranes is part of the pro-inflammatory response. Collectively, these results provide a molecular foundation for the clinical studies showing a beneficial effect of PC therapy in ulcerative colitis.
Treede
Irina
I
Department of Gastroenterology, University Hospital Heidelberg, INF 345, Heidelberg 69120, Germany, the; Cell Biology Program, European Molecular Biology Laboratory, Postfach 102209, Heidelberg 69117, Germany, the.
Braun
Annika
A
Department of Gastroenterology, University Hospital Heidelberg, INF 345, Heidelberg 69120, Germany, the.
Sparla
Richard
R
Department of Gastroenterology, University Hospital Heidelberg, INF 345, Heidelberg 69120, Germany, the.
Kühnel
Mark
M
Cell Biology Program, European Molecular Biology Laboratory, Postfach 102209, Heidelberg 69117, Germany, the.
Giese
Thomas
T
Institute of Immunology, University of Heidelberg, Im Neuenheimer Feld 305, Heidelberg 69120, Germany, the.
Turner
Jerrold R
JR
Department of Pathology, University of Chicago, MC-1089, 60637 Chicago, Illinois.
Anes
Elsa
E
Unidade dos Retrovirus e Infeccdoas Associades(URIA)-Molecular Pathogenesis Centre, Faculty of Pharmacy, University of Lisbon, av. das Forcas Armadas, Lisbon 1600-083, Portugal, and the.
Kulaksiz
Hasan
H
Department of Gastroenterology, University Hospital Heidelberg, INF 345, Heidelberg 69120, Germany, the.
Füllekrug
Joachim
J
Department of Gastroenterology, University Hospital Heidelberg, INF 345, Heidelberg 69120, Germany, the.
Stremmel
Wolfgang
W
Department of Gastroenterology, University Hospital Heidelberg, INF 345, Heidelberg 69120, Germany, the.
Griffiths
Gareth
G
Cell Biology Program, European Molecular Biology Laboratory, Postfach 102209, Heidelberg 69117, Germany, the.
Ehehalt
Robert
R
Department of Gastroenterology, University Hospital Heidelberg, INF 345, Heidelberg 69120, Germany, the. Electronic address: robert_ehehalt@med.uni-heidelberg.de.
D000199:Actins / Q000737:chemistry; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D018938:Caco-2 Cells; D016764:Cell Polarity; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D016328:NF-kappa B / Q000378:metabolism; D010588:Phagosomes / Q000378:metabolism; D010713:Phosphatidylcholines / Q000493:pharmacokinetics / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000199:Actins; D000893:Anti-Inflammatory Agents; D016328:NF-kappa B; D010713:Phosphatidylcholines; D014409:Tumor Necrosis Factor-alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases