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Dead cell-derived immunosuppressive molecule identified

Dead cell-derived prostaglandin E2 suppresses inflammation and promotes tumor growth

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Institute of Industrial Science
2016/03/29

© 2016 Sho Hangai.Dead cell-derived PGE2 functions as an inhibitory DAMP (iDAMP).  Immune responses to cell death are modulated by an interplay between iDAMP and activating DAMP (aDAMP).

Function of PGE2 released from dead cells
Dead cell-derived PGE2 functions as an inhibitory DAMP (iDAMP). Immune responses to cell death are modulated by an interplay between iDAMP and activating DAMP (aDAMP).
© 2016 Sho Hangai.

University of Tokyo researchers have demonstrated that prostaglandin E2 (PGE2) was released by various types of dead cells and this dead cell-derived PGE2 had critical roles in the pathogenesis of inflammation and cancer.

Upon cell death, nucleic acids and proteins are released, which in turn stimulate inflammatory response. These molecules are called damage associated molecular patterns (DAMPs) and associated with autoimmune diseases, atherosclerosis, cancer and neurodegenerative diseases through induction of immune response. Thus, DAMPs are the focus of much attention as therapeutic targets for these diseases. However, it has not been addressed whether inhibitory DAMP molecule(s) are also released to balance the magnitude of the inflammatory responses.

In this study, the research group of the University of Tokyo Graduate School of Medicine graduate student Sho Hangai and Institute of Industrial Science Project Associate Professor Hideyuki Yanai revealed that dead cells released PGE2, suppressing inflammation and immune responses. Indeed, suppressing the release of PGE2 from dead cells exacerbated dead cell-induced inflammation. In addition, inhibiting the production of PGE2 exacerbated the symptoms of mice suffering from liver failure and enhanced dead cell-induced inflammation, while inhibiting the production of PGE2 in cancer cells suppressed their growth.

“DAMPs have been attracting attention as a group of molecules that cause inflammation. This study is the first to identify an immunosuppressive DAMP and provide evidence for its role in an inflammatory disease and cancer,” explains Yanai. He continues, “Given that approximately 100,000 human cells in our body undergo cell death every second even when healthy, and massive cell death occurs in inflammatory diseases and cancer, the present study offers new insights into the maintenance of homeostatic conditions and pathogenesis of these diseases, and might lead to novel therapies for these diseases.”

The present research was carried out as part of the Faculty of Medicine MD researcher training program in conjunction with then-undergraduate student Tomoka Ao.

Paper

Sho Hangai, Tomoka Ao, Yoshitaka Kimura, Kosuke Matsuki, Takeshi Kawamura, Hideo Negishi, Junko Nishio, Tatsuhiko Kodama, Tadatsugu Taniguchi, and Hideyuki Yanai, "PGE2 induced in and released by dying cells functions as an inhibitory DAMP", Proceedings of the National Academy of Sciences Online Edition: 2016/03/22 (Japan time), doi: 10.1073/pnas.1602023113.
Article link (Publication)

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Institute of Industrial Science

Department of Molecular Immunology, Institute of Industrial Science

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