PMID- 23488692
OWN - NLM
STAT- MEDLINE
DCOM- 20130701
LR  - 20220331
IS  - 1365-3083 (Electronic)
IS  - 0300-9475 (Print)
IS  - 0300-9475 (Linking)
VI  - 77
IP  - 5
DP  - 2013 May
TI  - IL-1beta/HMGB1 complexes promote The PGE2 biosynthesis pathway in synovial 
      fibroblasts.
PG  - 350-60
LID - 10.1111/sji.12041 [doi]
AB  - PGE2 is a potent lipid mediator of pain and oedema found elevated in RA. 
      Microsomal prostaglandin E synthase-1 (mPGES-1) is a terminal enzyme of the PGE2 
      pathway inducible by proinflammatory cytokines. mPGES-1 is markedly upregulated 
      in RA synovial tissue despite antirheumatic treatments, suggesting that multiple 
      inflammatory stimuli contribute to its induction. High-mobility group box 
      chromosomal protein 1 (HMGB1) is known to induce inflammation both by direct 
      interaction with TLR4 and by enhancement of other proinflammatory molecules 
      signalling, through complex formation. The high expression of extracellular HMGB1 
      within the inflamed synovium, implies its pro-arthritogenic role in RA. We aimed 
      to investigate the effects of IL-1beta/HMGB1 complexes on mPGES-1 and other enzymes 
      of the PGE2 pathway in synovial fibroblasts (SFs) from patients with arthritis. 
      Furthermore, we studied the effect of COX-2 inhibition and IL-1RI antagonism on 
      prostanoid and cytokine production by SFs. Stimulation of SFs with HMGB1 in 
      complex with suboptimal amounts of IL-1beta significantly increased mPGES-1 and 
      COX-2 expressions as well as PGE2 production, as compared to treatment with HMGB1 
      or IL-1beta alone. Furthermore, NS-398 reduced the production of IL-6 and IL-8, thus 
      indicating that IL-1beta/HMGB1 complexes modulate cytokine production in part 
      through prostanoid synthesis. Treatment with IL-1RA completely abolished the 
      induced PGE2 and cytokine production, suggesting an effect mediated through 
      IL-1RI. IL-1beta/HMGB1 complexes promote the induction of mPGES-1, COX-2 and PGE2 in 
      SF. The amplification of the PGE2 biosynthesis pathway by HMGB1 might constitute 
      an important pathogenic mechanism perpetuating inflammatory and destructive 
      activities in rheumatoid arthritis.
CI  - (c) 2013 The Authors. Scandinavian Journal of Immunology (c) 2013 Blackwell 
      Publishing Ltd.
FAU - Leclerc, P
AU  - Leclerc P
AD  - Rheumatology Research Unit, Department of Medicine, Karolinska Institutet, 
      Stockholm, Sweden.
FAU - Wahamaa, H
AU  - Wahamaa H
FAU - Idborg, H
AU  - Idborg H
FAU - Jakobsson, P J
AU  - Jakobsson PJ
FAU - Harris, H E
AU  - Harris HE
FAU - Korotkova, M
AU  - Korotkova M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Scand J Immunol
JT  - Scandinavian journal of immunology
JID - 0323767
RN  - 0 (Chemokines)
RN  - 0 (Cyclooxygenase Inhibitors)
RN  - 0 (Cytokines)
RN  - 0 (HMGB1 Protein)
RN  - 0 (Interleukin 1 Receptor Antagonist Protein)
RN  - 0 (Interleukin-1beta)
RN  - 0 (Interleukin-6)
RN  - 0 (Interleukin-8)
RN  - 0 (Nitrobenzenes)
RN  - 0 (Sulfonamides)
RN  - 123653-11-2 (N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide)
RN  - EC 1.14.99.1 (Cyclooxygenase 2)
RN  - EC 1.14.99.1 (PTGS2 protein, human)
RN  - EC 5.3.- (Intramolecular Oxidoreductases)
RN  - EC 5.3.99.3 (PTGES protein, human)
RN  - EC 5.3.99.3 (Prostaglandin-E Synthases)
RN  - K7Q1JQR04M (Dinoprostone)
SB  - IM
MH  - Arthritis/metabolism/pathology
MH  - Biosynthetic Pathways/*drug effects
MH  - Blotting, Western
MH  - Cells, Cultured
MH  - Chemokines/metabolism
MH  - Cyclooxygenase 2/metabolism
MH  - Cyclooxygenase Inhibitors/pharmacology
MH  - Cytokines/metabolism
MH  - Dinoprostone/*biosynthesis
MH  - Drug Synergism
MH  - Fibroblasts/*drug effects/metabolism
MH  - HMGB1 Protein/*pharmacology
MH  - Humans
MH  - Interleukin 1 Receptor Antagonist Protein/pharmacology
MH  - Interleukin-1beta/*pharmacology
MH  - Interleukin-6/metabolism
MH  - Interleukin-8/*metabolism
MH  - Intramolecular Oxidoreductases/metabolism
MH  - Nitrobenzenes/pharmacology
MH  - Prostaglandin-E Synthases
MH  - Sulfonamides/pharmacology
MH  - Synovial Membrane/metabolism/pathology
PMC - PMC3670302
EDAT- 2013/03/16 06:00
MHDA- 2013/07/03 06:00
CRDT- 2013/03/16 06:00
PHST- 2012/12/18 00:00 [received]
PHST- 2013/02/15 00:00 [accepted]
PHST- 2013/03/16 06:00 [entrez]
PHST- 2013/03/16 06:00 [pubmed]
PHST- 2013/07/03 06:00 [medline]
AID - 10.1111/sji.12041 [doi]
PST - ppublish
SO  - Scand J Immunol. 2013 May;77(5):350-60. doi: 10.1111/sji.12041.