Disease-Association Analysis of an Inflammation-Related Feedback Loop

• Main Authors: 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
• Format: Article
• Language: English
• Published: Elsevier 2013-03-01
• Series: Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124713000521

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.