PMID- 11087727
OWN - NLM
STAT- MEDLINE
DCOM- 20010405
LR  - 20231213
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 276
IP  - 9
DP  - 2001 Mar 2
TI  - Tumor necrosis factor-alpha induces distinctive NF-kappa B signaling within human 
      dermal fibroblasts.
PG  - 6214-24
AB  - The TNF-alpha receptor-associated factor 2 (TRAF2) and its downstream mediator, 
      the NF-kappa B-inducing kinase (NIK), have been shown to induce NF-kappa B 
      activation in 293 cells. Investigating the role these mediators play in human 
      skin, we found that both NIK and TRAF2 failed to evoke transcription from 
      NF-kappa B-dependent promoters linked to the CAT reporter in human dermal 
      fibroblast cultures, while epidermal keratinocyte cultures demonstrated 
      NIK-dependent signaling. Further, NF-kappa B activation by TNF-alpha was 
      unaffected by overexpression of a dominant negative mutant NIK in fibroblasts, 
      despite detection of endogenous TRAF2 and NIK by Western analysis. To explore 
      alternative signaling mechanisms in dermal fibroblasts, we found that the 
      intracellular calcium chelator, 3,4,5-trimethoxybenzoic acid, and the calpain 
      inhibitor, N-acetyl-Leu-Leu-norleucinal, both blocked NF-kappa B activation; 
      however, the specific proteosome inhibitor, lactacystin, failed to do so. 
      Furthermore, TNF-alpha receptor mutants lacking a functional death domain failed 
      to stimulate NF-kappa B, while phosphatidylcholine-phospholipase C inhibition and 
      alkalization of endolysosomal compartments blocked its activation by TNF-alpha. 
      These data indicate that, while epidermal keratinocytes utilize previously 
      defined, NIK-dependent NF-kappa B pathways, dermal fibroblasts demonstrate unique 
      NIK/TRAF2-independent signal transduction, where both acidic sphingomyelinase and 
      calpain activity act as surrogate mediators for NF-kappa B activation.
FAU - Kouba, D J
AU  - Kouba DJ
AD  - Department of Dermatology, Jefferson Medical College, Thomas Jefferson 
      University, Philadelphia, Pennsylvania 19107, USA.
FAU - Nakano, H
AU  - Nakano H
FAU - Nishiyama, T
AU  - Nishiyama T
FAU - Kang, J
AU  - Kang J
FAU - Uitto, J
AU  - Uitto J
FAU - Mauviel, A
AU  - Mauviel A
LA  - eng
GR  - R01-AR41439/AR/NIAMS NIH HHS/United States
GR  - R29-AR43751/AR/NIAMS 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.
DEP - 20001121
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Arabidopsis Proteins)
RN  - 0 (Ceramides)
RN  - 0 (NF-kappa B)
RN  - 0 (Proteins)
RN  - 0 (TNF Receptor-Associated Factor 1)
RN  - 0 (TNF Receptor-Associated Factor 2)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 1.14.19.- (Fatty Acid Desaturases)
RN  - EC 1.14.99.- (Fad7 protein, Arabidopsis)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - *Arabidopsis Proteins
MH  - Calcium/physiology
MH  - Cells, Cultured
MH  - Ceramides/physiology
MH  - Fatty Acid Desaturases/physiology
MH  - Fibroblasts/drug effects/metabolism
MH  - Humans
MH  - NF-kappa B/*physiology
MH  - Protein Serine-Threonine Kinases/physiology
MH  - Proteins/physiology
MH  - Skin/cytology
MH  - TNF Receptor-Associated Factor 1
MH  - TNF Receptor-Associated Factor 2
MH  - Tumor Necrosis Factor-alpha/*pharmacology
MH  - NF-kappaB-Inducing Kinase
EDAT- 2000/11/23 00:00
MHDA- 2001/04/06 10:01
CRDT- 2000/11/23 00:00
PHST- 2000/11/23 00:00 [pubmed]
PHST- 2001/04/06 10:01 [medline]
PHST- 2000/11/23 00:00 [entrez]
AID - S0021-9258(19)34625-3 [pii]
AID - 10.1074/jbc.M004511200 [doi]
PST - ppublish
SO  - J Biol Chem. 2001 Mar 2;276(9):6214-24. doi: 10.1074/jbc.M004511200. Epub 2000 
      Nov 21.