A gp130–Src–YAP module links inflammation to epithelial regeneration

Koji Taniguchi, Li-Wha Wu, Sergei I. Grivennikov, Petrus R. de Jong, Ian Lian, Fa-Xing Yu, Kepeng Wang, Samuel B. Ho, Brigid S. Boland, John T. Chang, William J. Sandborn, Gary Hardiman, Eyal Raz, Yoshihiko Maehara, Akihiko Yoshimura, Jessica Zucman-Rossi, Kun-Liang Guan & Michael Karin

Nature 519, 57-62, 2015

Speaker: Wei-Kuan Sung (宋惟寬)               Time: 13:00~14:00 Dec. 23, 2015

Commentator: Dr. Li-Wha Wu (吳梨華 教授)     Place: Room 601

Abstract

        With changes in diet, there are more and more people getting the bowel diseases, including inflammatory bowel disease (IBD) and Crohn’s disease (CD).¹ Expression of interleukin (IL)-6 family members is elevated in many diseases, such as IBD and colorectal cancer.² However, the mechanism of inflammation in IBD is still unclear. In this study, the authors reported that IL-6 promoted intestinal epithelial cell (IEC) proliferation and regeneration. Moreover, IL-6-deficient mice did not exhibit developmental abnormalities. In mouse and human cells, gp130, a co-receptor for IL-6 cytokines, triggered activation of Yes-associated protein (YAP) and Notch, independently of the gp130 effector STAT3. The authors used dextran sulfate sodium salt (DSS)-induced mouse colitis model to elucidate the mechanism underlying the association between IL-6 and other proteins, such as gp130, Src, YAP and STAT3. In addition to STAT3 in IECs, YAP and Notch were activated after DSS challenge, resulting in mucosal regeneration. Through YAP and Notch, intestinal gp130 signalling stimulates epithelial cell proliferation, causes aberrant differentiation and confers resistance to mucosal erosion. gp130 is associated with the related tyrosine kinases Src and Yes. Subsequently, Yes is activated on receptor engagement to phosphorylate YAP and induce its stabilization and nuclear translocation. This signalling module is strongly activated upon mucosal injury to promote healing and maintain the barrier function. Thus, future therapeutic efforts in IBD should aim at normalizing IL-6 cytokine expression, rather than completing blockade, thereby restoring immune and epithelial homeostasis.

References

1.         Neurath, M. F. (2014) New targets for mucosal healing and therapy in inflammatory bowel diseases. Mucosal Immunol. 7: 6–19.

2.         Rose-John, S., Mitsuyama, K., Matsumoto, S., Thaiss, W. M. & Scheller, J. (2009) Interleukin-6 trans-signaling and colonic cancer associated with inflammatory bowel disease. Curr. Pharm. Des. 15: 2095–2103.