PMID- 9794459
OWN - NLM
STAT- MEDLINE
DCOM- 19981106
LR  - 20111027
IS  - 0013-7227 (Print)
IS  - 0013-7227 (Linking)
VI  - 139
IP  - 11
DP  - 1998 Nov
TI  - Role of nuclear factor-kappaB activation in cytokine- and 
      sphingomyelinase-stimulated inducible nitric oxide synthase gene expression in 
      vascular smooth muscle cells.
PG  - 4506-12
AB  - Inflammatory cytokines, such as interleukin-1beta (IL-1beta) and tumor necrosis 
      factor-alpha (TNF alpha), are known to activate sphingomyelinase (SMase) and 
      nuclear factor-kappaB (NF-kappaB) in certain cell types, which also stimulate 
      inducible nitric oxide synthase (iNOS) gene in vascular smooth muscle cells 
      (VSMCs). However, it remains unknown whether the SMase pathway is involved in 
      iNOS gene expression in VSMCs. Therefore, the present study was designed to 
      examine whether SMase induces iNOS gene expression via the NF-kappaB activation 
      pathway similar to that of IL-1beta and TNF alpha in cultured rat VSMCs. Neutral 
      SMase, although less potently than IL-1beta and TNF alpha, stimulated 
      nitrite/nitrate (NOx) production, and iNOS messenger RNA and protein expression, 
      as assessed by Northern and Western blot analyses, respectively. Neutral SMase, 
      IL-1beta, and TNF alpha activated NF-kappaB, as revealed by electrophoretic 
      mobility shift assay, and its nuclear translocation, as demonstrated by 
      immunocytochemical study. Neutral SMase potentiated NOx production, iNOS 
      expression, and NF-kappaB activation stimulated by TNF alpha, but not by 
      IL-1beta. Aldehyde peptide proteasome inhibitors completely blocked NOx 
      production, iNOS expression, NF-kappaB activation, and its nuclear translocation 
      induced by cytokines and neutral SMase. IL-1beta and TNF alpha, but not neutral 
      SMase, caused a transient decrease in IkappaB-alpha protein levels, whereas 
      IkappaB-beta protein expression was not affected by either agent. Proteasome 
      inhibitors prevented cytokine-mediated IkappaB-alpha degradation. Several 
      cell-permeable ceramide analogs (C2, C6, and C8), hydrolysis products of 
      sphingomyelin, activated NF-kappaB less potently than neutral SMase, but had no 
      effect on NOx production. These results demonstrate an essential role of 
      NF-kappaB activation in mediation of neutral SMase-induced iNOS expression, but 
      distinct from the proteasome-mediated IkappaB-alpha degradation by cytokines, 
      suggesting the possible involvement of an additional signaling pathway(s).
FAU - Katsuyama, K
AU  - Katsuyama K
AD  - Second Department of Internal Medicine, Tokyo Medical and Dental University, 
      Japan.
FAU - Shichiri, M
AU  - Shichiri M
FAU - Marumo, F
AU  - Marumo F
FAU - Hirata, Y
AU  - Hirata Y
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Endocrinology
JT  - Endocrinology
JID - 0375040
RN  - 0 (Cytokines)
RN  - 0 (NF-kappa B)
RN  - EC 1.14.13.39 (NOS2 protein, human)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type II)
RN  - EC 1.14.13.39 (Nos2 protein, rat)
RN  - EC 3.1.4.12 (Sphingomyelin Phosphodiesterase)
SB  - IM
MH  - Animals
MH  - Blotting, Northern
MH  - Blotting, Western
MH  - Cells, Cultured
MH  - Cytokines/*pharmacology
MH  - Electrophoresis, Polyacrylamide Gel
MH  - Enzyme Induction/drug effects
MH  - Humans
MH  - Immunohistochemistry
MH  - Male
MH  - Muscle, Smooth, Vascular/cytology/drug effects/*metabolism
MH  - NF-kappa B/*physiology
MH  - Nitric Oxide Synthase/*biosynthesis/genetics
MH  - Nitric Oxide Synthase Type II
MH  - Rats
MH  - Rats, Wistar
MH  - Sphingomyelin Phosphodiesterase/biosynthesis/*pharmacology
MH  - Translocation, Genetic/drug effects
EDAT- 1998/10/30 00:00
MHDA- 1998/10/30 00:01
CRDT- 1998/10/30 00:00
PHST- 1998/10/30 00:00 [pubmed]
PHST- 1998/10/30 00:01 [medline]
PHST- 1998/10/30 00:00 [entrez]
AID - 10.1210/endo.139.11.6309 [doi]
PST - ppublish
SO  - Endocrinology. 1998 Nov;139(11):4506-12. doi: 10.1210/endo.139.11.6309.