PMID- 26134265
OWN - NLM
STAT- MEDLINE
DCOM- 20151116
LR  - 20190816
IS  - 1096-0333 (Electronic)
IS  - 0041-008X (Print)
IS  - 0041-008X (Linking)
VI  - 287
IP  - 3
DP  - 2015 Sep 15
TI  - Thymoquinone inhibits TNF-alpha-induced inflammation and cell adhesion in rheumatoid 
      arthritis synovial fibroblasts by ASK1 regulation.
PG  - 299-305
LID - S0041-008X(15)30024-7 [pii]
LID - 10.1016/j.taap.2015.06.017 [doi]
AB  - Tumor necrosis factor-alpha (TNF-alpha) is a pro-inflammatory cytokine produced by 
      monocytes/macrophage that plays a pathological role in rheumatoid arthritis (RA). 
      In this study, we investigate the effect of thymoquinone (TQ), a phytochemical 
      found in Nigella sativa, in regulating TNF-alpha-induced RA synovial fibroblast 
      (RA-FLS) activation. Treatment with TQ (1-5muM) had no marked effect on the 
      viability of human RA-FLS. Pre-treatment of TQ inhibited TNF-alpha-induced 
      interleukin-6 (IL-6) and IL-8 production and ICAM-1, VCAM-1, and cadherin-11 
      (Cad-11) expression in RA-FLS (p<0.01). Evaluation of the signaling events showed 
      that TQ inhibited TNF-alpha-induced phospho-p38 and phospho-JNK expression, but had 
      no inhibitory effect on NF-kappaB pathway, in RA-FLS (p<0.05; n=4). Interestingly, we 
      observed that selective down-regulation of TNF-alpha-induced phospho-p38 and 
      phospho-JNK activation by TQ is elicited through inhibition of 
      apoptosis-regulated signaling kinase 1 (ASK1). Furthermore, TNF-alpha selectively 
      induced phosphorylation of ASK1 at Thr845 residue in RA-FLS, which was inhibited 
      by TQ pretreatment in a dose dependent manner (p<0.01). Pre-treatment of RA-FLS 
      with ASK1 inhibitor (TC ASK10), blocked TNF-alpha induced expression of ICAM-1, 
      VCAM-1, and Cad-11. Our results suggest that TNF-alpha-induced ASK1-p38/JNK pathway 
      is an important mediator of cytokine synthesis and enhanced expression of 
      adhesion molecule in RA-FLS and TQ, by selectively inhibiting this pathway, may 
      have a potential therapeutic value in regulating tissue destruction observed in 
      RA.
CI  - Copyright (c) 2015 Elsevier Inc. All rights reserved.
FAU - Umar, Sadiq
AU  - Umar S
AD  - Department of Pharmaceutical Sciences, Washington State University College of 
      Pharmacy, Spokane, WA, USA.
FAU - Hedaya, Omar
AU  - Hedaya O
AD  - Department of Pharmaceutical Sciences, Washington State University College of 
      Pharmacy, Spokane, WA, USA.
FAU - Singh, Anil K
AU  - Singh AK
AD  - Department of Pharmaceutical Sciences, Washington State University College of 
      Pharmacy, Spokane, WA, USA.
FAU - Ahmed, Salahuddin
AU  - Ahmed S
AD  - Department of Pharmaceutical Sciences, Washington State University College of 
      Pharmacy, Spokane, WA, USA. Electronic address: salah.ahmed@wsu.edu.
LA  - eng
GR  - R01 AR063104/AR/NIAMS NIH HHS/United States
GR  - AR063104/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150629
PL  - United States
TA  - Toxicol Appl Pharmacol
JT  - Toxicology and applied pharmacology
JID - 0416575
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Benzoquinones)
RN  - 0 (CXCL8 protein, human)
RN  - 0 (Cell Adhesion Molecules)
RN  - 0 (IL6 protein, human)
RN  - 0 (Inflammation Mediators)
RN  - 0 (Interleukin-6)
RN  - 0 (Interleukin-8)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.25 (MAP Kinase Kinase Kinase 5)
RN  - EC 2.7.11.25 (MAP3K5 protein, human)
RN  - O60IE26NUF (thymoquinone)
SB  - IM
MH  - Anti-Inflammatory Agents/*pharmacology
MH  - Arthritis, Rheumatoid/*enzymology/immunology/surgery
MH  - Benzoquinones/*pharmacology
MH  - Cell Adhesion/*drug effects
MH  - Cell Adhesion Molecules/immunology/metabolism
MH  - Cells, Cultured
MH  - Dose-Response Relationship, Drug
MH  - Enzyme Activation
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - Fibroblasts/*drug effects/enzymology/immunology
MH  - Humans
MH  - Inflammation Mediators/immunology/metabolism
MH  - Interleukin-6/immunology/metabolism
MH  - Interleukin-8/immunology/metabolism
MH  - MAP Kinase Kinase Kinase 5/immunology/*metabolism
MH  - Phosphorylation
MH  - Signal Transduction/drug effects
MH  - Synovial Membrane/*drug effects/enzymology/immunology
MH  - Tumor Necrosis Factor-alpha/*pharmacology
MH  - p38 Mitogen-Activated Protein Kinases/metabolism
PMC - PMC4549173
MID - NIHMS714626
OTO - NOTNLM
OT  - ASK1
OT  - MAP kinase
OT  - Rheumatoid arthritis
OT  - Synovial fibroblasts
OT  - TNF-alpha
OT  - Thymoquinone
COIS- CONFLICT OF INTEREST The authors declare no conflict of interest.
EDAT- 2015/07/03 06:00
MHDA- 2015/11/17 06:00
PMCR- 2016/09/15
CRDT- 2015/07/03 06:00
PHST- 2015/04/27 00:00 [received]
PHST- 2015/06/22 00:00 [revised]
PHST- 2015/06/23 00:00 [accepted]
PHST- 2015/07/03 06:00 [entrez]
PHST- 2015/07/03 06:00 [pubmed]
PHST- 2015/11/17 06:00 [medline]
PHST- 2016/09/15 00:00 [pmc-release]
AID - S0041-008X(15)30024-7 [pii]
AID - 10.1016/j.taap.2015.06.017 [doi]
PST - ppublish
SO  - Toxicol Appl Pharmacol. 2015 Sep 15;287(3):299-305. doi: 
      10.1016/j.taap.2015.06.017. Epub 2015 Jun 29.