Thymoquinone inhibits TNF-α-induced inflammation and cell adhesion in rheumatoid arthritis synovial fibroblasts by ASK1 regulation

Sadiq Umar; Omar Hedaya; Anil K Singh; Salahuddin Ahmed

doi:10.1016/j.taap.2015.06.017

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Thymoquinone inhibits TNF-α-induced inflammation and cell adhesion in rheumatoid arthritis synovial fibroblasts by ASK1 regulation

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Thymoquinone inhibits TNF-α-induced inflammation and cell adhesion in rheumatoid arthritis synovial fibroblasts by ASK1 regulation

Sadiq Umar, Omar Hedaya, Anil K Singh and Salahuddin Ahmed

Toxicology and applied pharmacology, Vol.287(3), pp.299-305

09/15/2015

DOI: https://doi.org/10.1016/j.taap.2015.06.017

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https://hdl.handle.net/2376/100888

PMCID: PMC4549173

PMID: 26134265

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Abstract

Arthritis, Rheumatoid - surgery

Fibroblasts - enzymology

Phosphorylation

Synovial Membrane - enzymology

Humans

Synovial Membrane - immunology

Synovial Membrane - drug effects

Cell Adhesion Molecules - immunology

Extracellular Signal-Regulated MAP Kinases - metabolism

Dose-Response Relationship, Drug

Inflammation Mediators - metabolism

p38 Mitogen-Activated Protein Kinases - metabolism

Interleukin-8 - metabolism

MAP Kinase Kinase Kinase 5 - metabolism

Interleukin-6 - metabolism

Inflammation Mediators - immunology

Anti-Inflammatory Agents - pharmacology

Cells, Cultured

Arthritis, Rheumatoid - enzymology

Cell Adhesion - drug effects

Cell Adhesion Molecules - metabolism

Benzoquinones - pharmacology

Tumor Necrosis Factor-alpha - pharmacology

Signal Transduction - drug effects

Fibroblasts - drug effects

Interleukin-6 - immunology

Fibroblasts - immunology

Enzyme Activation

Arthritis, Rheumatoid - immunology

Interleukin-8 - immunology

MAP Kinase Kinase Kinase 5 - immunology

Tumor necrosis factor-α (TNF-α) 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-α-induced RA synovial fibroblast (RA-FLS) activation. Treatment with TQ (1-5μM) had no marked effect on the viability of human RA-FLS. Pre-treatment of TQ inhibited TNF-α-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-α-induced phospho-p38 and phospho-JNK expression, but had no inhibitory effect on NF-κB pathway, in RA-FLS (p<0.05; n=4). Interestingly, we observed that selective down-regulation of TNF-α-induced phospho-p38 and phospho-JNK activation by TQ is elicited through inhibition of apoptosis-regulated signaling kinase 1 (ASK1). Furthermore, TNF-α 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-α induced expression of ICAM-1, VCAM-1, and Cad-11. Our results suggest that TNF-α-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.

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Title: Thymoquinone inhibits TNF-α-induced inflammation and cell adhesion in rheumatoid arthritis synovial fibroblasts by ASK1 regulation
Creators: Sadiq Umar - Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, WA, USA
Omar Hedaya - Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, WA, USA
Anil K Singh - Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, WA, USA
Salahuddin Ahmed - Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, WA, USA. Electronic address: salah.ahmed@wsu.edu
Publication Details: Toxicology and applied pharmacology, Vol.287(3), pp.299-305
Academic Unit: Pharmaceutical Sciences, Department of
Publisher: United States
Grant note: R01 AR063104 / NIAMS NIH HHS AR063104 / NIAMS NIH HHS
Identifiers: 99900546630501842
Language: English
Resource Type: Journal article