Computer model of IL-6-dependent rheumatoid arthritis in F759 mice

Author:

Yamamoto Reiji12,Yamada Satoshi3,Atsumi Toru1,Murakami Kaoru1,Hashimoto Ari4,Naito Seiichiro1,Tanaka Yuki15,Ohki Izuru5,Shinohara Yuta1,Iwasaki Norimasa2,Yoshimura Akihiko6,Jiang Jing-Jing1,Kamimura Daisuke1,Hojyo Shintaro1,Kubota Shimpei I1,Hashimoto Shigeru1,Murakami Masaaki1578

Affiliation:

1. Molecular Psychoneuroimmunology, Institute of Genetic Medicine, Hokkaido University , Sapporo , Japan

2. Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University , Sapporo , Japan

3. Faculty of Information Science and Engineering, Okayama University of Science , Okayama , Japan

4. Department of Molecular Biology, Hokkaido University Faculty of Medicine , Sapporo , Japan

5. Team of Quantum immunology, Institute for Quantum Life Science, National Institute for Quantum and Radiological Science and Technology (QST) , Chiba , Japan

6. Department of Microbiology and Immunology, School of Medicine, Keio University , Tokyo , Japan

7. Neuroimmunology, Department of Homeostatic Regulation, National Institute for Physiological Sciences, National Institutes of Natural Sciences , Aichi 444-8585 , Japan

8. Institute for Vaccine Research and Development (HU-IVReD), Hokkaido University , Sapporo 001 - 0020 , Japan

Abstract

Abstract The interleukin-6 (IL-6) amplifier, which describes the simultaneous activation of signal transducer and activator of transcription 3 (STAT3) and NF-κb nuclear factor kappa B (NF-κB), in synovial fibroblasts causes the infiltration of immune cells into the joints of F759 mice. The result is a disease that resembles human rheumatoid arthritis. However, the kinetics and regulatory mechanisms of how augmented transcriptional activation by STAT3 and NF-κB leads to F759 arthritis is unknown. We here show that the STAT3-NF-κB complex is present in the cytoplasm and nucleus and accumulates around NF-κB binding sites of the IL-6 promoter region and established a computer model that shows IL-6 and IL-17 (interleukin 17) signaling promotes the formation of the STAT3-NF-κB complex followed by its binding on promoter regions of NF-κB target genes to accelerate inflammatory responses, including the production of IL-6, epiregulin, and C-C motif chemokine ligand 2 (CCL2), phenotypes consistent with in vitro experiments. The binding also promoted cell growth in the synovium and the recruitment of T helper 17 (Th17) cells and macrophages in the joints. Anti-IL-6 blocking antibody treatment inhibited inflammatory responses even at the late phase, but anti-IL-17 and anti-TNFα antibodies did not. However, anti-IL-17 antibody at the early phase showed inhibitory effects, suggesting that the IL-6 amplifier is dependent on IL-6 and IL-17 stimulation at the early phase, but only on IL-6 at the late phase. These findings demonstrate the molecular mechanism of F759 arthritis can be recapitulated in silico and identify a possible therapeutic strategy for IL-6 amplifier-dependent chronic inflammatory diseases.

Funder

KAKENHI

Japan Agency for Medical Research and Development

AMED-CREST

Hokkaido University

Publisher

Oxford University Press (OUP)

Subject

Immunology,General Medicine,Immunology and Allergy

Cited by 2 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3