Regulation of rheumatoid synovial cell growth by ceramide.
Overgrowth of rheumatoid synoviocytes, which results in joint destruction, is due to impaired balance between cell proliferation and cell death (apoptosis). Ceramide is an important lipid messenger involved in mediating a variety of cell functions including apoptosis. We investigated the effects of ceramide on growth-promoting anti-apoptotic signals in rheumatoid synovial cells. Human synovial cells isolated from patients with rheumatoid arthritis (RA) were stimulated with platelet-derived growth factor (PDGF) in the presence or absence of C2-ceramide. The kinase activity of Akt, MEK, and ERK1/2 was analyzed in PDGF-stimulated synovial cells by Western blot analysis. Pretreatment with C2-ceramide completely inhibited PDGF-induced cell cycle progression of rheumatoid synovial cells. PDGF stimulation induced phosphorylation and activation of Akt, MEK, and ERK1/2 in rheumatoid synovial cells. C2-ceramide inhibited the activation of Akt, MEK and ERK1/2 in PDGF-stimulated synovial cells. Our data demonstrated that inhibition of anti-apoptotic kinases, such as Akt and ERK1/2, may play an important role in ceramide-mediated apoptosis of rheumatoid synovial cells.
Migita
K
K
First Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan.
Honda
S
S
Yamasaki
S
S
Hirai
Y
Y
Fukuda
T
T
Aoyagi
T
T
Kita
M
M
Ida
H
H
Tsukada
T
T
Kawakami
A
A
Kawabe
Y
Y
Eguchi
K
K
D017209:Apoptosis / Q000187:drug effects; D001172:Arthritis, Rheumatoid / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013583:Synovial Membrane / Q000187:drug effects* / Q000473:pathology*
C064769:N-acetylsphingosine; D010982:Platelet-Derived Growth Factor; D011518:Proto-Oncogene Proteins; D011494:Protein Kinases; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D013110:Sphingosine