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Sci. Signal., 17 January 2012
Vol. 5, Issue 207, p. ra5
[DOI: 10.1126/scisignal.2002056]

RESEARCH ARTICLES

Interleukin-11 Links Oxidative Stress and Compensatory Proliferation

Takashi Nishina1,2, Sachiko Komazawa-Sakon1, Saeko Yanaka3, Xuehua Piao1, Dong-Mei Zheng4,5, Jiang-Hu Piao1,5,6, Yuko Kojima7, Shunhei Yamashina8, Emiko Sano3,9, Tracy Putoczki10, Takahiro Doi11, Takashi Ueno4, Junji Ezaki4, Hiroko Ushio2, Matthias Ernst10, Kouhei Tsumoto3,9, Ko Okumura1,2, and Hiroyasu Nakano1*

1 Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
2 Atopy Research Center, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
3 Department of Medical Genome Sciences, School of Frontier Sciences, University of Tokyo, Kashiwa 277-8562, Japan.
4 Department of Biochemistry, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
5 Sportology Center, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
6 Department of Immunology, School of Basic Medical Science, Ningxia Medical College, 1160 Shengli Street, Xingqing-Qu, Yinchuan 750004, China.
7 Division of Biomedical Imaging Research, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
8 Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
9 The Institute of Medical Science, University of Tokyo, Kashiwa 277-8562, Japan.
10 Colon Molecular and Cell Biology Laboratory, Ludwig Institute for Cancer Research, PO Royal Melbourne Hospital, Melbourne, Victoria 3050, Australia.
11 Subteam for BioResponse Integration, RIKEN (Institute of Physical and Chemical Research), BioResource Center, Tsukuba, Ibaraki 305-0074, Japan.

Abstract: Apoptotic cells can stimulate the compensatory proliferation of surrounding cells to maintain tissue homeostasis. Although oxidative stress is associated with apoptosis and necrosis, whether it contributes to compensatory proliferation is unknown. Here, we showed that interleukin-11 (IL-11), a member of the IL-6 family of proinflammatory cytokines, was produced by cells in an oxidative stress–dependent manner. IL-11 production depended on the activation in dying cells of extracellular signal–regulated kinase 2, which in turn caused the phosphorylation and accumulation of the transcription factor Fra-1 by preventing its proteasome-dependent degradation. Fra-1 was subsequently recruited to the Il11 promoter and activated gene transcription. Upon acute liver injury in mice, IL-11 was mainly produced by hepatocytes in response to reactive oxygen species that were presumably released from dying hepatocytes. IL-11 that was secreted by the dying cells then induced the phosphorylation of the transcription factor STAT3 in adjacent healthy hepatocytes, which resulted in their compensatory proliferation. Furthermore, an IL-11 receptor (IL-11R) agonist enhanced the proliferation of hepatocytes and ameliorated oxidative stress upon acetaminophen-induced liver injury. Conversely, the effects of acetaminophen were exacerbated in mice deficient in the IL-11R α subunit. Together, these results suggest that IL-11 provides a functional link between oxidative stress and compensatory proliferation.

* To whom correspondence should be addressed. E-mail: hnakano{at}juntendo.ac.jp

Citation: T. Nishina, S. Komazawa-Sakon, S. Yanaka, X. Piao, D.-M. Zheng, J.-H. Piao, Y. Kojima, S. Yamashina, E. Sano, T. Putoczki, T. Doi, T. Ueno, J. Ezaki, H. Ushio, M. Ernst, K. Tsumoto, K. Okumura, H. Nakano, Interleukin-11 Links Oxidative Stress and Compensatory Proliferation. Sci. Signal. 5, ra5 (2012).

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
c-FLIP Maintains Tissue Homeostasis by Preventing Apoptosis and Programmed Necrosis.
X. Piao, S. Komazawa-Sakon, T. Nishina, M. Koike, J.-H. Piao, H. Ehlken, H. Kurihara, M. Hara, N. Van Rooijen, G. Schutz, et al. (2012)
Science Signaling 5, ra93
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