PMID- 8349660
OWN - NLM
STAT- MEDLINE
DCOM- 19930916
LR  - 20210210
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 268
IP  - 24
DP  - 1993 Aug 25
TI  - Tumor necrosis factor-alpha (TNF-alpha) signal transduction through ceramide. 
      Dissociation of growth inhibitory effects of TNF-alpha from activation of nuclear 
      factor-kappa B.
PG  - 17762-6
AB  - Tumor necrosis factor-alpha (TNF-alpha) exerts pleiotropic biologic effects. 
      Although TNF-alpha appears to activate a number of signal transduction pathways, 
      the role of second messengers in mediating the different effects of TNF-alpha are 
      not well defined. In this study, we investigated the role of ceramide as an 
      intracellular mediator of TNF-alpha action. In Jurkat T cells, TNF-alpha caused 
      early activation of the sphingomyelin cycle with peak hydrolysis of sphingomyelin 
      observed at 30 min following addition of TNF-alpha. In this cell line, TNF-alpha 
      caused potent activation of nuclear factor-kappa B (NF-kappa B) and exerted 
      potent cytostatic/cytocidal activity. C2-ceramide mimicked the effects of 
      TNF-alpha on cell growth in a dose-dependent manner, but C2-ceramide was unable 
      to induce activation of NF-kappa B under multiple conditions investigated. 
      C2-ceramide, however, enhanced activation of NF-kappa B in response to TNF-alpha 
      with peak effects observed at a concentration of C2-ceramide of 5 microM. Thus, 
      ceramide functions as a selective mediator of the cytostatic/cytotoxic effects of 
      TNF-alpha and plays a positive feedback role in activation of NF-kappa B. 
      TNF-alpha signaling, therefore, involves multiple second-messenger pathways that 
      function independently or coordinately to transduce distinct functions of 
      TNF-alpha.
FAU - Dbaibo, G S
AU  - Dbaibo GS
AD  - Department of Medicine, Duke University Medical Center, Durham, North Carolina 
      27710.
FAU - Obeid, L M
AU  - Obeid LM
FAU - Hannun, Y A
AU  - Hannun YA
LA  - eng
GR  - GM-43825/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Ceramides)
RN  - 0 (NF-kappa B)
RN  - 0 (Oligonucleotide Probes)
RN  - 0 (Receptors, Interleukin-2)
RN  - 0 (Sphingomyelins)
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Base Sequence
MH  - Binding Sites
MH  - Cell Nucleus/metabolism
MH  - Ceramides/*metabolism
MH  - Humans
MH  - Kinetics
MH  - Leukemia-Lymphoma, Adult T-Cell
MH  - Molecular Sequence Data
MH  - NF-kappa B/*metabolism
MH  - Oligonucleotide Probes
MH  - Promoter Regions, Genetic
MH  - Receptors, Interleukin-2/genetics
MH  - *Signal Transduction/drug effects
MH  - Sphingomyelins/*metabolism
MH  - Time Factors
MH  - Tumor Cells, Cultured
MH  - Tumor Necrosis Factor-alpha/*pharmacology
EDAT- 1993/08/25 00:00
MHDA- 1993/08/25 00:01
CRDT- 1993/08/25 00:00
PHST- 1993/08/25 00:00 [pubmed]
PHST- 1993/08/25 00:01 [medline]
PHST- 1993/08/25 00:00 [entrez]
AID - S0021-9258(17)46770-6 [pii]
PST - ppublish
SO  - J Biol Chem. 1993 Aug 25;268(24):17762-6.