PMID- 25229347
OWN - NLM
STAT- MEDLINE
DCOM- 20151217
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 9
IP  - 9
DP  - 2014
TI  - 5-Lipoxygenase inhibitors attenuate TNF-alpha-induced inflammation in human synovial 
      fibroblasts.
PG  - e107890
LID - 10.1371/journal.pone.0107890 [doi]
LID - e107890
AB  - The lipoxygenase isoform of 5-lipoxygenase (5-LOX) is reported to be 
      overexpressed in human rheumatoid arthritis synovial tissue and involved in the 
      progress of inflammatory arthritis. However, the detailed mechanism of how 
      5-lipoxygenase regulates the inflammatory response in arthritis synovial tissue 
      is still unclear. The aim of this study was to investigate the involvement of 
      lipoxygenase pathways in TNF-alpha-induced production of cytokines and chemokines. 
      Human synovial fibroblasts from rheumatoid patients were used in this study. 
      5-LOX inhibitors and shRNA were used to examine the involvement of 5-LOX in 
      TNF-alpha-induced cytokines and chemokines expression. The signaling pathways were 
      examined by Western Blotting or immunofluorescence staining. The effect of 5-LOX 
      inhibitor on TNF-alpha-induced chemokine expression and paw edema was also explored 
      in vivo in C57BL/6 mice. Treatment with 5-LOX inhibitors significantly decreased 
      TNF-alpha-induced pro-inflammatory mediators including interleukin-6 (IL-6) and 
      monocyte chemo-attractant protein-1 (MCP-1) in human synovial fibroblasts. 
      Knockdown of 5-LOX using shRNA exerted similar inhibitory effects. The abrogation 
      of NF-kappaB activation was involved in the antagonizing effects of these inhibitors. 
      Furthermore, 5-LOX inhibitor decreased TNF-alpha-induced up-regulation of serum MCP-1 
      level and paw edema in mouse model. Our results provide the evidence that the 
      administration of 5-LOX inhibitors is able to ameliorate TNF-alpha-induced 
      cytokine/chemokine release and paw edema, indicating that 5-LOX inhibitors may be 
      developed for therapeutic treatment of inflammatory arthritis.
FAU - Lin, Han-Ching
AU  - Lin HC
AD  - Department of Pharmacology, College of Medicine, National Taiwan University and 
      Hospital, Taipei, Taiwan.
FAU - Lin, Tzu-Hung
AU  - Lin TH
AD  - Department of Pharmacology, College of Medicine, National Taiwan University and 
      Hospital, Taipei, Taiwan.
FAU - Wu, Ming-Yueh
AU  - Wu MY
AD  - Department of Pharmacology, College of Medicine, National Taiwan University and 
      Hospital, Taipei, Taiwan.
FAU - Chiu, Yung-Cheng
AU  - Chiu YC
AD  - Department of Orthopaedics, Taichung Veterans General Hospital, Taichung, Taiwan.
FAU - Tang, Chih-Hsin
AU  - Tang CH
AD  - Department of Pharmacology, College of Medicine, China Medical University, 
      Taichung, Taiwan.
FAU - Hour, Mann-Jen
AU  - Hour MJ
AD  - School of Pharmacy, College of Medicine, China Medical University, Taichung, 
      Taiwan.
FAU - Liou, Houng-Chi
AU  - Liou HC
AD  - Department of Pharmacology, College of Medicine, National Taiwan University and 
      Hospital, Taipei, Taiwan.
FAU - Tu, Huang-Ju
AU  - Tu HJ
AD  - Department of Pharmacology, College of Medicine, National Taiwan University and 
      Hospital, Taipei, Taiwan.
FAU - Yang, Rong-Sen
AU  - Yang RS
AD  - Department of Orthopedics, College of Medicine, National Taiwan University and 
      Hospital, Taipei, Taiwan.
FAU - Fu, Wen-Mei
AU  - Fu WM
AD  - Department of Pharmacology, College of Medicine, National Taiwan University and 
      Hospital, Taipei, Taiwan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140917
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (CCL2 protein, human)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Interleukin-6)
RN  - 0 (Lipoxygenase Inhibitors)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 1HGW4DR56D (Leukotriene B4)
RN  - EC 1.13.11.34 (Arachidonate 5-Lipoxygenase)
RN  - EC 2.7.11.10 (CHUK protein, human)
RN  - EC 2.7.11.10 (I-kappa B Kinase)
RN  - EC 2.7.11.10 (IKBKB protein, human)
SB  - IM
MH  - Animals
MH  - Arachidonate 5-Lipoxygenase/deficiency/genetics/*metabolism
MH  - Chemokine CCL2/blood/genetics/metabolism
MH  - Edema/drug therapy/genetics/metabolism/pathology
MH  - Enzyme Activation/drug effects
MH  - Fibroblasts/*drug effects/metabolism
MH  - Gene Knockout Techniques
MH  - Humans
MH  - I-kappa B Kinase/metabolism
MH  - Inflammation/chemically induced/drug therapy/metabolism/pathology
MH  - Interleukin-6/genetics/metabolism
MH  - Leukotriene B4/metabolism
MH  - Lipoxygenase Inhibitors/*pharmacology/therapeutic use
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Phosphorylation/drug effects
MH  - Proteolysis/drug effects
MH  - RNA Interference
MH  - RNA, Small Interfering/genetics
MH  - Synovial Membrane/*pathology
MH  - Tumor Necrosis Factor-alpha/*adverse effects
PMC - PMC4168259
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2014/09/18 06:00
MHDA- 2015/12/19 06:00
PMCR- 2014/09/17
CRDT- 2014/09/18 06:00
PHST- 2014/05/06 00:00 [received]
PHST- 2014/08/14 00:00 [accepted]
PHST- 2014/09/18 06:00 [entrez]
PHST- 2014/09/18 06:00 [pubmed]
PHST- 2015/12/19 06:00 [medline]
PHST- 2014/09/17 00:00 [pmc-release]
AID - PONE-D-14-19336 [pii]
AID - 10.1371/journal.pone.0107890 [doi]
PST - epublish
SO  - PLoS One. 2014 Sep 17;9(9):e107890. doi: 10.1371/journal.pone.0107890. 
      eCollection 2014.