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Dexamethasone Suppresses Tumor Necrosis Factor--Induced Apoptosis in Osteoblasts: Possible Role for Ceramide¹

Department of Dental Pharmacology and Wonkwang Dental Research Institute, School of Dentistry, Wonkwang University (H.J.C., J.S.K., B.G.B., S.B.C., H.R.K.); Department of Pharmacology and Institute of Cardiovascular Research, School of Medicine, Chonbuk National University (H.J.C., S.W.C.); Department of Microbiology and Immunology, School of Medicine (R.K.P., H.S.S.), and Department of Oriental Pharmacy, College of Pharmacy (Y.K.K., H.M.K.), Center of Oriental Medicinal Science, Wonkwang University, Chonbuk 570–749, South Korea

Address all correspondence and requests for reprints to: Hyung-Ryong Kim, D.D.S., Ph.D., Department of Dental Pharmacology, Wonkwang University, School of Dentistry, Iksan, Chonbuk 570–749, South Korea. E-mail: hrkimdp{at}wonnms.wonkwang.ac.kr

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- (TNF-) activates the release of ceramide and that ceramide acts as a mediator for the TNF--induced stimulation of the binding affinity of nuclear factor-B (NF-B), 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--induced activation of NF-B, 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--induced JNK activation, ceramide elicits a more rapid activation of JNK within 30 min. C₂-ceramide activates NF-B and caspase-3 like protease to the same degree and with kinetics similar to those of TNF-. This study provides evidence that the release of ceramide may be required as a second messenger in TNF--induced apoptosis. These results also suggest a regulatory role for dexamethasone in TNF--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--related diseases, including rheumatoid arthritis and periodontitis.

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