title: Interleukin-11 links oxidative stress and compensatory proliferation.
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.
authors.affiliation: Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nishina
authors.forename: Sachiko
authors.initials: S
authors.lastname: Komazawa-Sakon
authors.forename: Saeko
authors.initials: S
authors.lastname: Yanaka
authors.forename: Xuehua
authors.initials: X
authors.lastname: Piao
authors.forename: Dong-Mei
authors.initials: DM
authors.lastname: Zheng
authors.forename: Jiang-Hu
authors.initials: JH
authors.lastname: Piao
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kojima
authors.forename: Shunhei
authors.initials: S
authors.lastname: Yamashina
authors.forename: Emiko
authors.initials: E
authors.lastname: Sano
authors.forename: Tracy
authors.initials: T
authors.lastname: Putoczki
authors.forename: Takahiro
authors.initials: T
authors.lastname: Doi
authors.forename: Takashi
authors.initials: T
authors.lastname: Ueno
authors.forename: Junji
authors.initials: J
authors.lastname: Ezaki
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ushio
authors.forename: Matthias
authors.initials: M
authors.lastname: Ernst
authors.forename: Kouhei
authors.initials: K
authors.lastname: Tsumoto
authors.forename: Ko
authors.initials: K
authors.lastname: Okumura
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Nakano
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D055106:Genome-Wide Association Study; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D017370:Interleukin-11 / Q000378:metabolism*; D051379:Mice; D008957:Models, Genetic; D018384:Oxidative Stress; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D053702:Receptors, Interleukin-11 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000099169:Fos-Related Antigen 1
chemical_list: D000082:Acetaminophen; D016207:Cytokines; D007375:Interleukin-1; D017370:Interleukin-11; D046988:Proteasome Endopeptidase Complex; D016760:Proto-Oncogene Proteins c-fos; D017382:Reactive Oxygen Species; D053702:Receptors, Interleukin-11; D050796:STAT3 Transcription Factor; D000099169:Fos-Related Antigen 1; C494087:Stat3 protein, mouse