1. Disease-Association Analysis of an Inflammation-Related Feedback Loop
- Author
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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, Yamauchi-Takihara, Keiko, Yamaguchi-Takihara, and Toshio, Hirano
- Subjects
Chemokine ,Multiple Sclerosis ,Transcription, Genetic ,Cell ,Disease Association ,Stimulation ,Inflammation ,Polymorphism, Single Nucleotide ,Epiregulin ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,Arthritis, Rheumatoid ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,SNP ,Animals ,Humans ,STAT3 ,Gene ,lcsh:QH301-705.5 ,Genetic Association Studies ,Positive feedback ,030304 developmental biology ,Feedback, Physiological ,0303 health sciences ,Genome ,biology ,Epidermal Growth Factor ,Interleukin-6 ,business.industry ,Epistasis, Genetic ,Genes, erbB-1 ,Feedback loop ,3. Good health ,Mice, Inbred C57BL ,medicine.anatomical_structure ,lcsh:Biology (General) ,Genetic Loci ,Immunology ,biology.protein ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
SummaryThe 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
- 2013