title: Disease-association analysis of an inflammation-related feedback loop.
abstract: 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.
authors: Laboratory of Developmental Immunology, JST-CREST, Graduate School of Frontier Biosciences, and WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan. murakami@molonc.med.osaka-u.ac.jp
authors: Masaaki
authors: M
authors: Murakami
authors: Masaya
authors: M
authors: Harada
authors: Daisuke
authors: D
authors: Kamimura
authors: Hideki
authors: H
authors: Ogura
authors: Yuko
authors: Y
authors: Okuyama
authors: Noriko
authors: N
authors: Kumai
authors: Azusa
authors: A
authors: Okuyama
authors: Rajeev
authors: R
authors: Singh
authors: Jing-Jing
authors: JJ
authors: Jiang
authors: Toru
authors: T
authors: Atsumi
authors: Sayaka
authors: S
authors: Shiraya
authors: Yuji
authors: Y
authors: Nakatsuji
authors: Makoto
authors: M
authors: Kinoshita
authors: Hitoshi
authors: H
authors: Kohsaka
authors: Makoto
authors: M
authors: Nishida
authors: Saburo
authors: S
authors: Sakoda
authors: Nobuyuki
authors: N
authors: Miyasaka
authors: Keiko
authors: K
authors: Yamauchi-Takihara
authors: Keiko
authors: K
authors: Yamaguchi-Takihara
authors: Toshio
authors: T
authors: Hirano
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D066260:Epiregulin; D004843:Epistasis, Genetic; D025461:Feedback, Physiological; D018773:Genes, erbB-1 / Q000235:genetics; D056726:Genetic Association Studies; D056426:Genetic Loci; D016678:Genome; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: C587880:EREG protein, human; D066260:Epiregulin; C587881:Ereg protein, mouse; D015850:Interleukin-6; C577686:interleukin-6, mouse; D004815:Epidermal Growth Factor