TY - JOUR
T1 - Disease-association analysis of an inflammation-related feedback loop
AU - Murakami, Masaaki
AU - Harada, Masaya
AU - Kamimura, Daisuke
AU - Ogura, Hideki
AU - Okuyama, Yuko
AU - Kumai, Noriko
AU - Okuyama, Azusa
AU - Singh, Rajeev
AU - Jiang, Jing Jing
AU - Atsumi, Toru
AU - Shiraya, Sayaka
AU - Nakatsuji, Yuji
AU - Kinoshita, Makoto
AU - Kohsaka, Hitoshi
AU - Nishida, Makoto
AU - Sakoda, Saburo
AU - Miyasaka, Nobuyuki
AU - Yamaguchi-Takihara, Keiko
AU - Hirano, Toshio
N1 - Funding Information:
We thank Dr. Katsuhiko Ishihara (Kawasaki Medical University) for providing us critical information about the culturing of human type 1 collagen + cells. We also thank Dr. Masatatsu Ogura (Hosei University) for providing us various critical statistical advices. We appreciate the excellent technical assistance provided by Ms. Eri Yoshimoto (Tokyo Medical and Dental University), and thank Ms. Ryoko Masuda (Osaka University) for her excellent secretarial assistance and Dr. Hideyuki Iwai for applying the Ethics Committees of Osaka University Hospital and Tokyo Medical and Dental University. We thank Dr. Peter Karagiannis (Osaka University) and Dr. Daniel W. Nebert (University of Cincinnati) for carefully reading the manuscript. We are grateful to Dr. Kenji Okonogi (Osaka University) for important suggestions on the data analyses of the screening results. We also thank Mr. Hironao Suzuki (Osaka University), Dr. Eri Sanda (Osaka University), and Dr. Chika Kitabayashi (Osaka University) for data entry of the genome-wide screening. This work was supported by KAKENHI (to M.H., D.K., H.O., M.M., and T.H.), the CREST Program of the Japan Science and Technology Agency (to T.H. and M.M.), and the Osaka Foundation for the Promotion of Clinical Immunology (to M.M.). M.M. and T.H. are listed as inventors in patent applications closely related to results in this paper.
PY - 2013
Y1 - 2013
N2 - The IL-6-triggered positive feedback loop for NF. κB 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 NF. κB and STAT3 and. induces chemokines and inflammation via an NF. κB 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. The IL-6 amplifier is activated by NF. κB and STAT3 and induces chemokines and inflammation. Murakami, Hirano, and colleagues have combined two functional genomics screens in mice with SNP-based disease association studies, finding 1,700 genes linked to the amplifier. These include 492 indications of association with human ailments beyond autoimmune diseases. The authors followed up on ErbB1 signaling, finding that it suppressed the IL-6 amplifier, whereas the expression of epiregulin, an ErbB1 ligand, was higher in patients with inflammatory diseases. Thus, the IL-6 amplifier is associated with human diseases, and the identified genes may be potential therapeutic targets.
AB - The IL-6-triggered positive feedback loop for NF. κB 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 NF. κB and STAT3 and. induces chemokines and inflammation via an NF. κB 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. The IL-6 amplifier is activated by NF. κB and STAT3 and induces chemokines and inflammation. Murakami, Hirano, and colleagues have combined two functional genomics screens in mice with SNP-based disease association studies, finding 1,700 genes linked to the amplifier. These include 492 indications of association with human ailments beyond autoimmune diseases. The authors followed up on ErbB1 signaling, finding that it suppressed the IL-6 amplifier, whereas the expression of epiregulin, an ErbB1 ligand, was higher in patients with inflammatory diseases. Thus, the IL-6 amplifier is associated with human diseases, and the identified genes may be potential therapeutic targets.
UR - http://www.scopus.com/inward/record.url?scp=84875814613&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2013.01.028
DO - 10.1016/j.celrep.2013.01.028
M3 - 学術論文
C2 - 23434511
AN - SCOPUS:84875814613
SN - 2639-1856
VL - 3
SP - 946
EP - 959
JO - Cell Reports
JF - Cell Reports
IS - 3
ER -
