Dexamethasone suppresses tumor necrosis factor-alpha-induced apoptosis in osteoblasts: possible role for ceramide.
Ceramide has been proposed as a second messenger molecule implicated in a variety of biological processes, including apoptosis. Recently, it has been reported that tumor necrosis factor-alpha (TNF-alpha) activates the release of ceramide and that ceramide acts as a mediator for the TNF-alpha-induced stimulation of the binding affinity of nuclear factor-KB (NF-KB), a ubiquitous transcription factor of particular importance in immune and inflammatory responses. In this study we demonstrate that dexamethasone, which reduces the production of ceramide, significantly inhibits TNF-alpha-induced activation of NF-KB, c-Jun N-terminal kinase, also known as stress-activating protein kinase, caspase-3-like cysteine protease, redistribution of cytochrome c, and apoptosis in MC3T3E1 osteoblasts. Compared with TNF-alpha-induced JNK activation, ceramide elicits a more rapid activation of JNK within 30 min. C2-ceramide activates NF-KB and caspase-3 like protease to the same degree and with kinetics similar to those of TNF-alpha. This study provides evidence that the release of ceramide may be required as a second messenger in TNF-alpha-induced apoptosis. These results also suggest a regulatory role for dexamethasone in TNF-alpha-induced apoptosis via inhibition of ceramide release. Therefore, our in vitro results suggest that therapies targeted at the inhibition of ceramide release may abrogate inflammatory processes in TNF-alpha-related diseases, including rheumatoid arthritis and periodontitis.
Chae
H J
HJ
Department of Dental Pharmacology and Wonkwang Dental Research Institute, School of Dentistry, Wonkwang University, Chonbuk, South Korea.
Chae
S W
SW
Kang
J S
JS
Bang
B G
BG
Cho
S B
SB
Park
R K
RK
So
H S
HS
Kim
Y K
YK
Kim
H M
HM
Kim
H R
HR
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002518:Ceramides / Q000494:pharmacology / Q000502:physiology*; D003574:Cytochrome c Group / Q000378:metabolism; D053938:DNA Fragmentation; D003907:Dexamethasone / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010006:Osteoblasts / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D002518:Ceramides; D003574:Cytochrome c Group; D005938:Glucocorticoids; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases