PMID- 9920026
OWN - NLM
STAT- MEDLINE
DCOM- 19990204
LR  - 20151119
IS  - 0004-3591 (Print)
IS  - 0004-3591 (Linking)
VI  - 42
IP  - 1
DP  - 1999 Jan
TI  - Enhancement of phosphorylation and transcriptional activity of the glucocorticoid 
      receptor in human synovial fibroblasts by nimesulide, a preferential 
      cyclooxygenase 2 inhibitor.
PG  - 157-66
AB  - OBJECTIVE: To examine the effect of 2 nonsteroidal antiinflammatory drugs 
      (NSAIDs), nimesulide (NIM), a preferential cyclooxygenase 2 (COX-2) inhibitor, 
      and naproxen (NAP), on the functional parameters and transcriptional activity of 
      the glucocorticoid receptor (GR) system in cultured human synovial fibroblasts 
      (HSF). METHODS: HSF were incubated with NIM (0.3, 3, and 30 microg/ml), NAP (15, 
      30, and 90 microg/ml), and dexamethasone (DEX; 0.01, 0.1, and 1 microM) on a 
      time- and dose-dependent basis. The numbers of GR binding sites per cell were 
      determined by radioligand receptor assay. Total cellular, cytoplasmic, or nuclear 
      GR protein was measured by Western analysis using a specific anti-human GR 
      antibody. Phosphorylation of GR was determined by specific immunoprecipitation of 
      protein extracts from 32P-orthophosphate-labeled HSF. Mitogen-activated protein 
      kinase p44/42 (MAPK) phosphorylation was followed by Western analysis using a 
      specific anti-phosphoMAPK antibody. Levels of activated nuclear GR capable of 
      binding specifically to a 32P-labeled oligonucleotide harboring the 
      glucocorticoid/hormone response element (GRE) were evaluated by gel 
      electrophoretic mobility shift analysis. The effects of NIM and DEX on 
      transcriptional activation of the mouse mammary tumor virus (MMTV) promoter was 
      determined by transfecting HSF with MMTV-luciferase (reporter gene) constructs. 
      RESULTS: NIM had no effect on the number of GR binding sites, in contrast to NAP 
      and DEX. NIM and NAP did not influence cellular GR protein levels or 
      nucleocytoplasmic shuttling, although DEX lowered GR messenger RNA and protein 
      levels after 48 hours. NIM, but not NAP, markedly increased MAPK phosphorylation 
      (suggesting an increase in MAPK cascade activity), GR phosphorylation, GR binding 
      to GRE, and transcriptional activation of MMTV promoter through the GRE site in 
      the promoter. CONCLUSION: This study is the first to report that the 
      antiinflammatory effects of NIM, an NSAID, may be partly related to its 
      activation of the GR system.
FAU - Di Battista, J A
AU  - Di Battista JA
AD  - University of Montreal, and Centre de Recherche L. C. Simard, Centre Hospitalier 
      de l'Universite de Montreal, Quebec, Canada.
FAU - Zhang, M
AU  - Zhang M
FAU - Martel-Pelletier, J
AU  - Martel-Pelletier J
FAU - Fernandes, J
AU  - Fernandes J
FAU - Alaaeddine, N
AU  - Alaaeddine N
FAU - Pelletier, J P
AU  - Pelletier JP
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Arthritis Rheum
JT  - Arthritis and rheumatism
JID - 0370605
RN  - 0 (Cyclooxygenase Inhibitors)
RN  - 0 (Receptors, Glucocorticoid)
RN  - 0 (Sulfonamides)
RN  - V4TKW1454M (nimesulide)
SB  - IM
MH  - Blotting, Western
MH  - Cyclooxygenase Inhibitors/*pharmacology
MH  - Electrophoresis, Gel, Two-Dimensional
MH  - Fibroblasts/metabolism
MH  - Humans
MH  - Mammary Tumor Virus, Mouse/genetics
MH  - Osteoarthritis/metabolism/pathology
MH  - Phosphorylation
MH  - Promoter Regions, Genetic
MH  - Radioligand Assay
MH  - Receptors, Glucocorticoid/genetics/immunology/*metabolism
MH  - Response Elements
MH  - Sulfonamides/*pharmacology
MH  - Synovial Fluid/*cytology
MH  - Transcription, Genetic/drug effects
MH  - Transcriptional Activation
MH  - Transfection
EDAT- 1999/01/27 00:00
MHDA- 1999/01/27 00:01
CRDT- 1999/01/27 00:00
PHST- 1999/01/27 00:00 [pubmed]
PHST- 1999/01/27 00:01 [medline]
PHST- 1999/01/27 00:00 [entrez]
AID - 10.1002/1529-0131(199901)42:1<157::AID-ANR19>3.0.CO;2-P [doi]
PST - ppublish
SO  - Arthritis Rheum. 1999 Jan;42(1):157-66. doi: 
      10.1002/1529-0131(199901)42:1<157::AID-ANR19>3.0.CO;2-P.