Disease-Association Analysis of an Inflammation-Related Feedback Loop

Masaaki Murakami; Masaya Harada; Daisuke Kamimura; Hideki Ogura; Yuko Okuyama; Noriko Kumai; Azusa Okuyama; Rajeev Singh; Jing-Jing Jiang; Toru Atsumi; Sayaka Shiraya; Yuji Nakatsuji; Makoto Kinoshita; Hitoshi Kohsaka; Makoto Nishida; Saburo Sakoda; Nobuyuki Miyasaka; Keiko Yamaguchi-Takihara; Toshio Hirano

doi:10.1016/j.celrep.2013.01.028

Cell Reports (Mar 2013)

Disease-Association Analysis of an Inflammation-Related Feedback Loop

Masaaki Murakami,
Masaya Harada,
Daisuke Kamimura,
Hideki Ogura,
Yuko Okuyama,
Noriko Kumai,
Azusa Okuyama,
Rajeev Singh,
Jing-Jing Jiang,
Toru Atsumi,
Sayaka Shiraya,
Yuji Nakatsuji,
Makoto Kinoshita,
Hitoshi Kohsaka,
Makoto Nishida,
Saburo Sakoda,
Nobuyuki Miyasaka,
Keiko Yamaguchi-Takihara,
Toshio Hirano

Affiliations

Masaaki Murakami: Laboratory of Developmental Immunology, JST-CREST, Graduate School of Frontier Biosciences, Graduate School of Medicine, and WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan
Masaya Harada: Laboratory of Developmental Immunology, JST-CREST, Graduate School of Frontier Biosciences, Graduate School of Medicine, and WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan
Daisuke Kamimura: Laboratory of Developmental Immunology, JST-CREST, Graduate School of Frontier Biosciences, Graduate School of Medicine, and WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan
Hideki Ogura: Laboratory of Developmental Immunology, JST-CREST, Graduate School of Frontier Biosciences, Graduate School of Medicine, and WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan
Yuko Okuyama: Laboratory of Developmental Immunology, JST-CREST, Graduate School of Frontier Biosciences, Graduate School of Medicine, and WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan
Noriko Kumai: Laboratory of Developmental Immunology, JST-CREST, Graduate School of Frontier Biosciences, Graduate School of Medicine, and WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan
Azusa Okuyama: Laboratory of Developmental Immunology, JST-CREST, Graduate School of Frontier Biosciences, Graduate School of Medicine, and WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan
Rajeev Singh: Laboratory of Developmental Immunology, JST-CREST, Graduate School of Frontier Biosciences, Graduate School of Medicine, and WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan
Jing-Jing Jiang: Laboratory of Developmental Immunology, JST-CREST, Graduate School of Frontier Biosciences, Graduate School of Medicine, and WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan
Toru Atsumi: Laboratory of Developmental Immunology, JST-CREST, Graduate School of Frontier Biosciences, Graduate School of Medicine, and WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan
Sayaka Shiraya: Laboratory of Developmental Immunology, JST-CREST, Graduate School of Frontier Biosciences, Graduate School of Medicine, and WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan
Yuji Nakatsuji: Department of Neurology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
Makoto Kinoshita: Department of Neurology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
Hitoshi Kohsaka: Department of Medicine and Rheumatology, GCOE Program, International Research Center for Molecular Science in Tooth and Bone Diseases, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
Makoto Nishida: Health Care Center, Osaka University, Osaka 560-0043, Japan
Saburo Sakoda: Department of Neurology, National Hospital Organization Toneyama Hospital, Osaka 560-0045, Japan
Nobuyuki Miyasaka: Department of Medicine and Rheumatology, GCOE Program, International Research Center for Molecular Science in Tooth and Bone Diseases, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
Keiko Yamaguchi-Takihara: Health Care Center, Osaka University, Osaka 560-0043, Japan
Toshio Hirano: JST-CREST, Osaka University, Osaka 565-0871, Japan

DOI: https://doi.org/10.1016/j.celrep.2013.01.028
Journal volume & issue: Vol. 3, no. 3
pp. 946 – 959

Abstract

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The IL-6-triggered positive feedback loop for NFκB signaling (or the IL-6 amplifier/Inflammation amplifier) was originally discovered as a synergistic-activation signal that follows IL-17/IL-6 stimulation in nonimmune cells. Subsequent results from animal models have shown that the amplifier is activated by stimulation of NFκB and STAT3 and induces chemokines and inflammation via an NFκB loop. However, its role in human diseases is unclear. Here, we combined two genome-wide mouse screens with SNP-based disease association studies, revealing 1,700 genes related to the IL-6 amplifier, 202 of which showed 492 indications of association with ailments beyond autoimmune diseases. We followed up on ErbB1 from our list. Blocking ErbB1 signaling suppressed the IL-6 amplifier, whereas the expression of epiregulin, an ErbB1 ligand, was higher in patients with inflammatory diseases. These results indicate that the IL-6 amplifier is indeed associated with human diseases and disorders and that the identified genes may make for potential therapeutic targets.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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