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Disease-Association Analysis of an Inflammation-Related Feedback Loop

The IL-6-triggered positive feedback loop for NFkB signaling (or the 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 NFkB and STAT3 and induces chemokines and inflammation via an NFkB 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 inflammation 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 inflammation amplifier, whereas the expression of epiregulin, an ErbB1 ligand, was higher in patients with inflammatory diseases. These results indicate that the inflammation amplifier is indeed associated with human diseases and disorders and that the identified genes may make for potential therapeutic targets.

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, and Toshio Hirano# (*, equal contribution; #, correspondence)
Disease-Association Analysis of an Inflammation-Related Feedback Loop.
Cell Reports. 3: 946-959, 2013 (PubMed)

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Achievements

Disease-Association Analysis of an Inflammation-Related Feedback Loop