PMID- 23072581
OWN - NLM
STAT- MEDLINE
DCOM- 20130823
LR  - 20211021
IS  - 1476-5381 (Electronic)
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 168
IP  - 6
DP  - 2013 Mar
TI  - Suppression of PU.1-linked TLR4 expression by cilostazol with decrease of 
      cytokine production in macrophages from patients with rheumatoid arthritis.
PG  - 1401-11
LID - 10.1111/bph.12021 [doi]
AB  - BACKGROUND AND PURPOSE: The present study assessed the effects of cilostazol on 
      LPS-stimulated TLR4 signal pathways in synovial macrophages from patients with 
      rheumatoid arthritis (RA). These effects were confirmed in collagen-induced 
      arthritis (CIA) in mice. EXPERIMENTAL APPROACH: Expression of TLR4, PU.1, NF-kappaB 
      p65 and IkappaBalpha on synovial fluid macrophages from RA patients was determined by 
      Western blotting, and cytokines were measured by ELISA. Anti-arthritic effects 
      were evaluated in CIA mice. KEY RESULTS: Intracellular cAMP was 
      concentration-dependently raised by cilostazol (1-100 muM). Cilostazol 
      significantly suppressed LPS-stimulated increase of TLR4 expression by blocking 
      PU.1 transcriptional activity in RA macrophages. In addition, cilostazol 
      decreased LPS-induced myeloid differentiation factor 88 (MyD88) expression, but 
      not that of TNF receptor-associated factor 6 (TRAF6). Cilostazol also suppressed 
      IkBalpha degradation and NF-kappaB p65 nuclear translocation. Moreover, LPS-induced 
      increase of cytokine production (TNF-alpha, IL-1beta) was inhibited by cilostazol, an 
      effect which was accompanied by suppression of IkappaBalpha degradation, and NF-kappaB p65 
      nuclear translocation. However, expression of anti-inflammatory IL-10 was 
      elevated by cilostazol and forskolin/IBMX. In mice with CIA, post-treatment with 
      cilostazol (30 mg kg(-)(1) day(-)(1)) decreased expression of TLR4 in knee joints in 
      association with decreased recruitment of macrophages. Consequently, synovial 
      inflammation, proteoglycan depletion and bone erosion were significantly 
      inhibited by cilostazol treatment. CONCLUSIONS AND IMPLICATIONS: Cilostazol 
      down-regulated LPS-stimulated PU.1-linked TLR4 expression and TLR4/MyD88/NF-kappaB 
      signal pathways, and then suppressed inflammatory cytokine production in synovial 
      macrophages from RA patients. Also cilostazol markedly inhibited the severity of 
      CIA in mice.
CI  - (c) 2012 The Authors. British Journal of Pharmacology (c) 2012 The British 
      Pharmacological Society.
FAU - Park, S Y
AU  - Park SY
AD  - Medical Research Center for Ischemic Tissue Regeneration, School of Medicine, 
      Pusan National University, Gyeongsangnam-do, Korea.
FAU - Lee, S W
AU  - Lee SW
FAU - Baek, S H
AU  - Baek SH
FAU - Lee, C W
AU  - Lee CW
FAU - Lee, W S
AU  - Lee WS
FAU - Rhim, B Y
AU  - Rhim BY
FAU - Hong, K W
AU  - Hong KW
FAU - Kim, C D
AU  - Kim CD
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (Antirheumatic Agents)
RN  - 0 (Cytokines)
RN  - 0 (Phosphodiesterase 3 Inhibitors)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (TLR4 protein, human)
RN  - 0 (Tetrazoles)
RN  - 0 (Tlr4 protein, mouse)
RN  - 0 (Toll-Like Receptor 4)
RN  - 0 (Trans-Activators)
RN  - 0 (proto-oncogene protein Spi-1)
RN  - N7Z035406B (Cilostazol)
SB  - IM
MH  - Animals
MH  - Antirheumatic Agents/*pharmacology/therapeutic use
MH  - Arthritis, Rheumatoid/*drug therapy/immunology/metabolism/pathology
MH  - Cells, Cultured
MH  - Cilostazol
MH  - Cytokines/antagonists & inhibitors/genetics/metabolism
MH  - Disease Models, Animal
MH  - Female
MH  - Gene Expression Regulation/drug effects
MH  - Humans
MH  - Knee Joint/drug effects/immunology/metabolism/pathology
MH  - Macrophage Activation/drug effects
MH  - Macrophages/*drug effects/immunology/metabolism/pathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred DBA
MH  - Phosphodiesterase 3 Inhibitors/*pharmacology/therapeutic use
MH  - Proto-Oncogene Proteins/*antagonists & inhibitors/genetics/metabolism
MH  - Second Messenger Systems/drug effects
MH  - Tetrazoles/*pharmacology/therapeutic use
MH  - Toll-Like Receptor 4/*antagonists & inhibitors/genetics/metabolism
MH  - Trans-Activators/*antagonists & inhibitors/genetics/metabolism
PMC - PMC3596645
EDAT- 2012/10/18 06:00
MHDA- 2013/08/24 06:00
PMCR- 2014/03/01
CRDT- 2012/10/18 06:00
PHST- 2011/10/11 00:00 [received]
PHST- 2012/07/30 00:00 [revised]
PHST- 2012/10/07 00:00 [accepted]
PHST- 2012/10/18 06:00 [entrez]
PHST- 2012/10/18 06:00 [pubmed]
PHST- 2013/08/24 06:00 [medline]
PHST- 2014/03/01 00:00 [pmc-release]
AID - 10.1111/bph.12021 [doi]
PST - ppublish
SO  - Br J Pharmacol. 2013 Mar;168(6):1401-11. doi: 10.1111/bph.12021.