A pro-inflammatory role for A20 and ABIN family proteins in human fibroblast-like synoviocytes in rheumatoid arthritis

Hideya Igarashi; Ayano Yahagi; Taro Saika; Jun Hashimoto; Tetsuya Tomita; Hideki Yoshikawa; Katsuhiko Ishihara

doi:10.1016/j.imlet.2011.10.011

A pro-inflammatory role for A20 and ABIN family proteins in human fibroblast-like synoviocytes in rheumatoid arthritis

Immunol Lett. 2012 Jan 30;141(2):246-53. doi: 10.1016/j.imlet.2011.10.011. Epub 2011 Nov 9.

Authors

Hideya Igarashi¹, Ayano Yahagi, Taro Saika, Jun Hashimoto, Tetsuya Tomita, Hideki Yoshikawa, Katsuhiko Ishihara

Affiliation

¹ Department of Immunology and Molecular Genetics, Kawasaki Medical School, 577 Matsushima, Kurashiki City, Okayama 701-0192, Japan.

PMID: 22093807
DOI: 10.1016/j.imlet.2011.10.011

Abstract

Circuit of chronic inflammation in the joints of rheumatoid arthritis (RA) starts from the production of inflammatory cytokines by fibroblast-like synoviocytes (FLS) stimulated by TNFα produced by inflammatory cells mainly composed of macrophages. In this context, TNFα/NF-κB pathway plays an essential role for the transcription of pro-inflammatory cytokines. Here we show that the kinetics of pro-inflammatory cytokine genes induced by TNFα in FLS from RA was synchronized with that of A20, ABIN1, and ABIN3 that have been thought as negative regulators for NF-κB activation. Furthermore, based on this finding, we could tentatively categorize the RA-FLS into two groups; TNFα low-responder and high-responder FLS. The high responders that have abundant mRNA levels of NF-κB inhibitory molecules were also accompanied with the marked induction of the pro-inflammatory cytokines by the stimulation with TNFα. The low responders RA-FLS did not show this property, nor did FLS from osteoarthritis. Phosphorylation dependent degradation of IκBα as well as NF-κB activation upon stimulation with TNFα was significantly enhanced in the high-responder FLS lines. Surprisingly, single transfection of each NF-κB inhibitor was enough to facilitate the transcription of pro-inflammatory cytokines, suggesting that there is an unknown pro-inflammatory function for A20 and ABIN family proteins in RA-FLS.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Arthritis, Rheumatoid / immunology*
Cells, Cultured
DNA-Binding Proteins / genetics
DNA-Binding Proteins / immunology
DNA-Binding Proteins / metabolism*
Fibroblasts / immunology
Fibroblasts / metabolism*
Fibroblasts / pathology
Humans
Inflammation
Inflammation Mediators / metabolism
Interleukin-1beta / genetics
Interleukin-1beta / immunology
Interleukin-1beta / metabolism
Interleukin-6 / genetics
Interleukin-6 / immunology
Interleukin-6 / metabolism
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / immunology
Intracellular Signaling Peptides and Proteins / metabolism*
NF-kappa B / immunology
NF-kappa B / metabolism
Nuclear Proteins / genetics
Nuclear Proteins / immunology
Nuclear Proteins / metabolism*
Proteins / genetics
Proteins / immunology
Proteins / metabolism*
Signal Transduction / immunology
Synovial Membrane / pathology
Transcriptional Activation / genetics
Transgenes / genetics
Tumor Necrosis Factor alpha-Induced Protein 3
Tumor Necrosis Factor-alpha / immunology
Tumor Necrosis Factor-alpha / metabolism

Substances

DNA-Binding Proteins
Inflammation Mediators
Interleukin-1beta
Interleukin-6
Intracellular Signaling Peptides and Proteins
NF-kappa B
Nuclear Proteins
Proteins
TNIP1 protein, human
TNIP3 protein, human
Tumor Necrosis Factor-alpha
TNFAIP3 protein, human
Tumor Necrosis Factor alpha-Induced Protein 3