Disease-association analysis of an inflammation-related feedback loop

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

Research output: Contribution to journalArticlepeer-review

43 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)946-959
Number of pages14
JournalCell Reports
Volume3
Issue number3
DOIs
Publication statusPublished - 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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