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.

Targeting Interleukin-11 Receptor-α Impairs Human Endometrial Cancer Cell Proliferation and Invasion In Vitro and Reduces Tumor Growth and Metastasis In Vivo

“…Furthermore, from immunohistologic analysis of tumors and flow cytometry performed on HEC1A cells, it was evident that IL11 blockade also promoted apoptosis. It is well known that IL11 can play an antiapoptotic role (32) and here we have demonstrated that IL11 blockade induces apoptosis in endometrial tumor xenografts. Considerable evidence suggests that IL11 is also required for epithelial cell proliferation and survival, leading to the initiation and progression of cancer in the gastric mucosa and colon in humans and mice (21).…”

“…In the cycling human endometrium, IL11 is regulated by prostaglandin E(2) (43). In other epithelial tumor types, IL11 is regulated by hypoxia (44) and oxidative stress (32). Although hypoxia did not alter IL11 levels in endometrial cancer cell lines (unpublished observations).…”

Extracellular nucleotides from dying cells act as molecular signals to promote wound repair in renal tubular injury

“…Previous studies have shown that the inflammatory cytokine IL-6 (33), chemokine monocyte chemoattractant protein-1 (16), and damage-associated molecular patterns (2) are also important features associated with the pathophysiology of AKI. Nishina et al (34) reported that IL-11, an IL-6 family cytokine released from damaged hepatic cells, provides a functional link between oxidative stress and "compensatory proliferation" after acetylp-aminophenol-induced liver injury. Additional studies are required to define the roles of these molecules in mediating homeostasis of tubular structures.…”

Molecular Pathways: IL11 as a Tumor-Promoting Cytokine—Translational Implications for Cancers

“…There is also emerging evidence for a role of IL11 in liver cancer, and akin to its role in gastrointestinal cancers, possibly evolving from a wound-healing mechanism. Upon acute liver injury and exposure to reactive oxygen species, we have shown in mice that IL11 is produced and released from dying hepatocytes to induce STAT3 activation in adjacent healthy hepatocytes to mediate their compensatory proliferation (52). Accordingly, this wound-healing reaction is impaired in IL11Ra-deficient mice (52), and expression of IL11, but not IL6, is increased in inflammatory hepatocellular adenomas (53).…”

“…Upon acute liver injury and exposure to reactive oxygen species, we have shown in mice that IL11 is produced and released from dying hepatocytes to induce STAT3 activation in adjacent healthy hepatocytes to mediate their compensatory proliferation (52). Accordingly, this wound-healing reaction is impaired in IL11Ra-deficient mice (52), and expression of IL11, but not IL6, is increased in inflammatory hepatocellular adenomas (53). Incidentally, inflammatory hepatocellular adenomas are also frequently associated with constitutively active somatic mutations of GP130 or of STAT3 (53,54).…”