Ultrashort echo time time-spatial labeling inversion pulse magnetic resonance angiography with denoising deep learning reconstruction for the assessment of abdominal visceral arteries.

Current contrast-enhanced magnetic resonance angiography (MRA) and non-contrast-enhanced balanced steady-state free precession (bSSFP) MRA cause susceptibility artifacts from metallic devices in assessing endovascular visceral-artery interventions. The aims of this study are to investigate and compare image quality (IQ) and susceptibility artifacts of three-dimensional (3D) ultrashort echo time (UTE) time-spatial labeling inversion pulse (Time-SLIP) with those of 3D bSSFP Time-SLIP and to assess denoising deep learning reconstruction (dDLR) for the improvement of the signal-to-noise ratio (SNR) in 3D UTE with sparse sampling in phantoms and human subjects. This is a prospective type of study. Pulsatile glycerin-water flow phantom with platinum-tungsten-alloy coil, stainless-steel, nitinol, and cobalt-alloy stents were used. Ten healthy volunteers (seven males) and three patients (two males) were included in this study. 3D UTE Time-SLIP and 3D bSSFP Time-SLIP at 3T were used. The phantom-based study compared the signal-intensity ratio of the device levels (SRdevice ) and distal segments (SRdistal ) to the proximal segments. The volunteer-based study measured SNR, contrast ratio (CR), and IQ. The patient study evaluated local artifacts from metallic devices. Statistical tests included paired t-tests, Wilcoxon-signed rank tests, and Kruskal-Wallis tests. In the phantom-based study, SRdevice was small with UTE Time-SLIP, except the stainless-steel stent. SRdistal was greater (49.1%-90.4%) on bSSFP images than UTE images (-11.1% to 9.6%). Among volunteers, dDLR in UTE images improved SNR (p < 0.05) and IQ (p < 0.05), but CR was unaffected. UTE Time-SLIP showed inferior SNR and IQ than bSSFP Time-SLIP in images with and without dDLR (p < 0.05 for each). However, among patients, UTE Time-SLIP showed reduced metal artifacts compared to bSSFP Time-SLIP. Irrespective of the lower SNR and IQ of 3D UTE Time-SLIP than those of 3D bSSFP Time-SLIP, the former appeared to better depict flow after stenting or coiling. This indicates the potential of 3D UTE Time-SLIP to provide suitable diagnostic images of target vessels. dDLR improved SNR with reducing artifacts related to radial sampling, while maintaining the contrast. LEVEL OF EVIDENCE: 2. TECHNICAL EFFICACY STAGE: 2.

A murine model of acute lung injury identifies growth factors to promote tissue repair and their biomarkers.

Type II alveolar epithelial cells (AEC2s) play a crucial role in the regeneration of type I AECs after acute lung injury. The mechanisms underlying the regeneration of AEC2s are not fully understood. To address this issue, here, we investigated a murine model of acute lung injury using mice expressing human Diphtheria Toxin Receptor (DTR) under the control of Lysozyme M promoter (LysM-DTR). DT injection induced the depletion of AEC2s, alveolar macrophages, and bone marrow (BM)-derived myeloid cells in LysM-DTR mice, and the mice died within 6 days after DT injection. Apoptotic AEC2s and bronchiolar epithelial cells appeared at 24 hr, whereas Ki67-positive proliferating cells appeared in the alveoli and bronchioles in the lung of LysM-DTR mice at 72-96 hr after DT injection. Transfer of wild-type BM cells into LysM-DTR mice accelerated the regeneration of AEC2s along with the up-regulation of several growth factors. Moreover, several metabolites were significantly decreased in the sera of LysM-DTR mice compared with WT mice after DT injection, suggesting that these metabolites might be biomarkers to predict AEC2s injury. Together, LysM-DTR mice might be useful to identify growth factors to promote lung repair and the metabolites to predict the severity of lung injury.

Critical Contribution of Nuclear Factor Erythroid 2-related Factor 2 (NRF2) to Electrophile-induced Interleukin-11 Production.

Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that plays a crucial role in protection of cells from electrophile-induced toxicity through up-regulating phase II detoxifying enzymes and phase III transporters. We previously reported that oxidative stress induces up-regulation of interleukin-11 (IL-11), a member of the IL-6 family that ameliorates acetaminophen-induced liver toxicity. However, a role for IL-11 in protection of cells from electrophile-induced toxicity remains unclear. Here we show that an environmental electrophile, 1,2-naphthoquinone (1,2-NQ), but not 15d-prostaglandin J2 (PGJ2) or tert-butylhydroxyquinone (tBHQ), induced IL-11 production. Consistent with a crucial role for prolonged ERK activation in H2O2-induced IL-11 production, 1,2-NQ, but not 15d-PGJ2 or tBHQ, elicited prolonged ERK activation. Conversely, inhibition of the ERK pathway by a MEK inhibitor completely blocked 1,2-NQ-induced IL-11 production at both protein and mRNA levels, further substantiating an intimate cross-talk between ERK activation and 1,2-NQ-induced IL-11 production. Promoter analysis of the Il11 gene revealed that two AP-1 sites were essential for 1,2-NQ-induced promoter activities. Among various members of the AP-1 family, Fra-1 was up-regulated by 1,2-NQ, and its up-regulation was blocked by a MEK inhibitor. Although NRF2 was not required for H2O2-induced IL11 up-regulation, NRF2 was essential for 1,2-NQ-induced IL11 up-regulation by increasing Fra-1 proteins possibly through promoting mRNA translation of FOSL1 Finally, intraperitoneal administration of 1,2-NQ induced body weight loss in wild-type mice, which was further exacerbated in Il11ra1-/- mice compared with Il11ra1+/- mice. Together, both Fra-1 and NRF2 play crucial roles in IL-11 production that protects cells from 1,2-NQ intestinal toxicity.

Generation of and characterization of anti-IL-11 antibodies using newly established Il11-deficient mice.

Interleukin (IL)-11 belongs to the members of the IL-6 family of cytokines and is involved in a variety of biological responses, including hematopoiesis, bone development, and carcinogenesis. However, the cellular sources of IL-11 and regulation of IL-11 expression under physiological and pathological conditions are not fully understood. One of the causes to prevent characterization of IL-11 in vivo is due to the lack of reliable antibodies that detect IL-11 by immunohistochemistry. Moreover, although mice lacking Il11ra have been generated and extensively characterized, Il11-deficient mice have not been characterized yet. Here we generated two anti-IL-11 antibodies that blocked biological activities of IL-11 and detected IL-11 by immunohistochemistry, respectively. One clone of anti-IL-11 antibodies blocked IL-11-, but not IL-6-induced cell proliferation and IL-11-induced phosphorylation of STAT3 of an IL-11-dependent cell line. Moreover, we used recently established Il11-deficient mice to test the specificity of anti-IL-11 antibodies for immunohistochemistry. Another clone of anti-IL-11 antibodies stained stromal cells surrounding tumors of the colon of wild-type, but not Il11-deficient mice following treatment with Azoxymethane plus dextran sulfate sodium. Together, these newly developed anti-IL-11 antibodies provide a better understanding of the functions of IL-11 in vivo under various physiological and pathological conditions.

[Distortion Reduction Effect of View Angle Tilting (VAT) in Large Field of View Magnetic Resonance Imaging].

With shortening of the gantry of magnetic resonance imaging (MRI) systems, large field-of-view (FOV) imaging has become difficult because static magnetic field nonuniformity and gradient magnetic field nonlinearity exacerbate geometric distortion of MR images. However, results of earlier studies have demonstrated that view angle tilting (VAT) can reduce severe image distortion attributable to local susceptibility effects of metals. Although VAT is usually applied to local magnetic field nonuniformity, in principle VAT is expected to correct distortion also for peripheral images in large-FOV MRI. Results from this phantom experiment using VAT with large-FOV verified the effectiveness of distortion correction. The experiment using VAT showed reduction of maximum distortion from 23.6 to -1.9 mm. Furthermore, results of a volunteer study confirmed the distortion correction capability of VAT: it reduced distortion and improved visibility of the anatomical structure. In conclusion, experimentally obtained results underscore VAT effectiveness for improving distortion in large-FOV MRI.

[The Measurement Precision and Accuracy of T1 Mapping Using Polarity Corrected (PC) TI Prep Tool].

The aim of this study was to evaluate the measurement precision and accuracy of T1 mapping using a polarity corrected (PC) TI prep tool, which was based on fast field echo (FFE) and obtained one data point with one inversion recovery (IR) pulse. A phantom was used consisting of eight materials with different Gd concentrations. T1 mappings were measured by changing the trigger interval and the inversion time (TI) interval. The T1 mapping measurement precision using the PC TI prep tool increased as the trigger interval was made longer. The measurement precision didn't depend on the interval of TI. On the other hand, when the trigger intervals are more than 1000 ms, the measurement accuracy was less than approximately 8%. By setting the optimal end of TI, the T1 mapping using a PC TI prep tool could measure the T1 value precisely and accurately.

Interleukin 11 confers resistance to dextran sulfate sodium-induced colitis in mice.

Intestinal homeostasis is tightly regulated by epithelial cells, leukocytes, and stromal cells, and its dysregulation is associated with inflammatory bowel diseases. Interleukin (IL)-11, a member of the IL-6 family of cytokines, is produced by inflammatory fibroblasts during acute colitis. However, the role of IL-11 in the development of colitis is still unclear. Herein, we showed that IL-11 ameliorated DSS-induced acute colitis in mouse models. We found that deletion of Il11ra1 or Il11 rendered mice highly susceptible to DSS-induced colitis compared to the respective control mice. The number of apoptotic epithelial cells was increased in DSS-treated Il11ra1- or Il11-deficient mice. Moreover, we showed that IL-11 production was regulated by reactive oxygen species (ROS) produced by lysozyme M-positive myeloid cells. These findings indicate that fibroblast-produced IL-11 plays an important role in protecting the mucosal epithelium in acute colitis. Myeloid cell-derived ROS contribute to the attenuation of colitis through the production of IL-11.

Fibroblast growth factor 18 stimulates the proliferation of hepatic stellate cells, thereby inducing liver fibrosis.

Liver fibrosis results from chronic liver injury triggered by factors such as viral infection, excess alcohol intake, and lipid accumulation. However, the mechanisms underlying liver fibrosis are not fully understood. Here, we demonstrate that the expression of fibroblast growth factor 18 (Fgf18) is elevated in mouse livers following the induction of chronic liver fibrosis models. Deletion of Fgf18 in hepatocytes attenuates liver fibrosis; conversely, overexpression of Fgf18 promotes liver fibrosis. Single-cell RNA sequencing reveals that overexpression of Fgf18 in hepatocytes results in an increase in the number of Lrat+ hepatic stellate cells (HSCs), thereby inducing fibrosis. Mechanistically, FGF18 stimulates the proliferation of HSCs by inducing the expression of Ccnd1. Moreover, the expression of FGF18 is correlated with the expression of profibrotic genes, such as COL1A1 and ACTA2, in human liver biopsy samples. Thus, FGF18 promotes liver fibrosis and could serve as a therapeutic target to treat liver fibrosis.

Importin ß1 protein-mediated nuclear localization of death receptor 5 (DR5) limits DR5/tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced cell death of human tumor cells.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/death receptor 5 (DR5)-mediated cell death plays an important role in the elimination of tumor cells and transformed cells. Recently, recombinant TRAIL and agonistic anti-DR5 monoclonal antibodies have been developed and applied to cancer therapy. However, depending on the type of cancer, the sensitivity to TRAIL has been reportedly different, and some tumor cells are resistant to TRAIL-mediated apoptosis. Using confocal microscopy, we found that large amounts of DR5 were localized in the nucleus in HeLa and HepG2 cells. Moreover, these tumor cells were resistant to TRAIL, whereas DU145 cells, which do not have nuclear DR5, were highly sensitive to TRAIL. By means of immunoprecipitation and Western blot analysis, we found that DR5 and importin ß1 were physically associated, suggesting that the nuclear DR5 was transported through the nuclear import pathway mediated by importin ß1. Two functional nuclear localization signals were identified in DR5, the mutation of which abrogated the nuclear localization of DR5 in HeLa cells. Moreover, the nuclear transport of DR5 was also prevented by the knockdown of importin ß1 using siRNA, resulting in the up-regulation of DR5 expression on the cell surface and an increased sensitivity of HeLa and HepG2 cells to TRAIL. Taken together, our findings suggest that the importin ß1-mediated nuclear localization of DR5 limits the DR5/TRAIL-induced cell death of human tumor cells and thus can be a novel target to improve cancer therapy with recombinant TRAIL and anti-DR5 antibodies.

IκBζ controls IL-17-triggered gene expression program in intestinal epithelial cells that restricts colonization of SFB and prevents Th17-associated pathologies.

Control of gut microbes is crucial for not only local defense in the intestine but also proper systemic immune responses. Although intestinal epithelial cells (IECs) play important roles in cytokine-mediated control of enterobacteria, the underlying mechanisms are not fully understood. Here we show that deletion of IκBζ in IECs in mice leads to dysbiosis with marked expansion of segmented filamentous bacteria (SFB), thereby enhancing Th17 cell development and exacerbating inflammatory diseases. Mechanistically, the IκBζ deficiency results in decrease in the number of Paneth cells and impairment in expression of IL-17-inducible genes involved in IgA production. The decrease in Paneth cells is caused by aberrant activation of IFN-γ signaling and a failure of IL-17-dependent recovery from IFN-γ-induced damage. Thus, the IL-17R-IκBζ axis in IECs contributes to the maintenance of intestinal homeostasis by serving as a key component in a regulatory loop between the gut microbiota and immune cells.

Interleukin-11-expressing fibroblasts have a unique gene signature correlated with poor prognosis of colorectal cancer.

Interleukin (IL)-11 is a member of the IL-6 family of cytokines and is involved in multiple cellular responses, including tumor development. However, the origin and functions of IL-11-producing (IL-11+) cells are not fully understood. To characterize IL-11+ cells in vivo, we generate Il11 reporter mice. IL-11+ cells appear in the colon in murine tumor and acute colitis models. Il11ra1 or Il11 deletion attenuates the development of colitis-associated colorectal cancer. IL-11+ cells express fibroblast markers and genes associated with cell proliferation and tissue repair. IL-11 induces the activation of colonic fibroblasts and epithelial cells through phosphorylation of STAT3. Human cancer database analysis reveals that the expression of genes enriched in IL-11+ fibroblasts is elevated in human colorectal cancer and correlated with reduced recurrence-free survival. IL-11+ fibroblasts activate both tumor cells and fibroblasts via secretion of IL-11, thereby constituting a feed-forward loop between tumor cells and fibroblasts in the tumor microenvironment.

Inhibition of Importin ß1 Augments the Anticancer Effect of Agonistic Anti-Death Receptor 5 Antibody in TRAIL-resistant Tumor Cells.

TNF-related apoptosis-inducing ligand (TRAIL) and an agonistic antibody against the death-inducing TRAIL receptor 5, DR5, are thought to selectively induce tumor cell death and therefore, have gained attention as potential therapeutics currently under investigation in several clinical trials. However, some tumor cells are resistant to TRAIL/DR5-induced cell death, even though they express DR5. Previously, we reported that DR5 is transported into the nucleus by importin ß1, and knockdown of importin ß1 upregulates cell surface expression of DR5 resulting in increased TRAIL sensitivity in vitro Here, we examined the impact of importin ß1 knockdown on agonistic anti-human DR5 (hDR5) antibody therapy. Drug-inducible importin ß1 knockdown sensitizes HeLa cells to TRAIL-induced cell death in vitro, and exerts an antitumor effect when combined with agonistic anti-hDR5 antibody administration in vivo Therapeutic importin ß1 knockdown, administered via the atelocollagen delivery system, as well as treatment with the importin ß inhibitor, importazole, induced regression and/or eradication of two human TRAIL-resistant tumor cells when combined with agonistic anti-hDR5 antibody treatment. Thus, these findings suggest that the inhibition of importin ß1 would be useful to improve the therapeutic effects of agonistic anti-hDR5 antibody against TRAIL-resistant cancers.

Regenerating islet-derived protein (Reg)3ß plays a crucial role in attenuation of ileitis and colitis in mice.

Regenerating islet-derived protein (Reg)3ß belongs to a member of the Reg family of proteins and has pleiotropic functions, including antimicrobial activity and tissue repair. However, whether Reg3ß plays a protective role in the development of colitis and ileitis has not been fully investigated. We generated transgenic mice expressing a short form of cellular FLICE-inhibitory protein (cFLIPs) that promotes necroptosis, a regulated form of cell death. cFLIPs transgenic (CFLARs Tg) mice develop severe ileitis in utero. Although Reg3ß is undetectable in the small intestine of wild-type embryos, its expression is aberrantly elevated in the small intestine of CFLARs Tg embryos. To test whether elevated Reg3ß attenuates or exacerbates ileitis in CFLARs Tg mice, we generated a Reg3b -/- strain. Reg3b -/- mice grew to adulthood without apparent abnormalities. Deletion of Reg3b in CFLARs Tg mice exacerbated the embryonic lethality of CFLARs Tg mice. Dextran sulfate sodium-induced colitis, characterized by body weight loss and infiltration of neutrophils, was exacerbated in Reg3b -/- compared to wild-type mice. Moreover, the expression of Interleukin 6, an inflammatory cytokine and Chitinase-like 3, a marker for tissue repair macrophages was elevated in the colon of Reg3b -/- mice compared to wild-type mice after DSS treatment. Together, these results suggest that attenuation of colitis and ileitis is a result of Reg3ß's real function.

NIK is involved in constitutive activation of the alternative NF-kappaB pathway and proliferation of pancreatic cancer cells.

Pancreatic cancer has one of the poorest prognoses among human neoplasms. Constitutive activation of NF-kappaB is frequently observed in pancreatic cancer cells and is involved in their malignancy. However, little is known about the molecular mechanism of this constitutive NF-kappaB activation. Here, we show that the alternative pathway is constitutively activated and NF-kappaB-inducing kinase (NIK), a mediator of the alternative pathway, is significantly expressed in pancreatic cancer cells. siRNA-mediated silencing of NIK expression followed by subcellular fractionation revealed that NIK is constitutively involved in the processing of p100 and nuclear transport of p52 and RelB in pancreatic cancer cells. In addition, NIK silencing significantly suppressed proliferation of pancreatic cancer cells. These results clearly indicate that NIK is involved in the constitutive activation of the alternative pathway and controls cell proliferation in pancreatic cancer cells. Therefore, NIK might be a novel target for the treatment of pancreatic cancer.

JunB plays a crucial role in development of regulatory T cells by promoting IL-2 signaling.

The AP-1 transcription factor JunB plays crucial roles in multiple biological processes, including placental formation and bone homeostasis. We recently reported that JunB is essential for development of Th17 cells, and thus Junb-deficient mice are resistant to experimental autoimmune encephalomyelitis. However, the role of JunB in CD4+ T cells under other inflammatory disease conditions is unknown. Here we show that mice lacking JunB in CD4+ T cells (Junbfl/flCd4-Cre mice) were more susceptible to dextran sulfate sodium (DSS)-induced colitis because of impaired development of regulatory T (Treg) cells. Production of interleukin (IL)-2 and expression of CD25, a high affinity IL-2 receptor component, were decreased in Junb-deficient CD4+ T cells in vitro and in vivo. Naive CD4+ T cells from Junbfl/flCd4-Cre mice failed to differentiate into Treg cells in the absence of exogenously added IL-2 in vitro. A mixed bone marrow transfer experiment revealed that defective Treg development of Junb-deficient CD4+ T cells was not rescued by co-transferred wild-type cells, indicating a significance of the cell-intrinsic defect. Injection of IL-2-anti-IL-2 antibody complexes induced expansion of Treg cells and alleviated DSS-induced colitis in Junbfl/flCd4-Cre mice. Thus JunB plays a crucial role in the development of Treg cells by facilitating IL-2 signaling.

Necroptosis of Intestinal Epithelial Cells Induces Type 3 Innate Lymphoid Cell-Dependent Lethal Ileitis.

A short form of cellular FLICE-inhibitory protein encoded by CFLARs promotes necroptosis. Although necroptosis is involved in various pathological conditions, the detailed mechanisms are not fully understood. Here we generated transgenic mice wherein CFLARs was integrated onto the X chromosome. All male CFLARs Tg mice died perinatally due to severe ileitis. Although necroptosis was observed in various tissues of CFLARs Tg mice, large numbers of intestinal epithelial cells (IECs) died by apoptosis. Deletion of Ripk3 or Mlkl, essential genes of necroptosis, prevented both necroptosis and apoptosis, and rescued lethality of CFLARs Tg mice. Type 3 innate lymphoid cells (ILC3s) were activated and recruited to the small intestine along with upregulation of interleukin-22 (Il22) in CFLARs Tg mice. Deletion of ILC3s or Il22 rescued lethality of CFLARs Tg mice by preventing apoptosis, but not necroptosis of IECs. Together, necroptosis-dependent activation of ILC3s induces lethal ileitis in an IL-22-dependent manner.

Novel method to rescue a lethal phenotype through integration of target gene onto the X-chromosome.

The loss-of-function mutations of serine protease inhibitor, Kazal type 1 (SPINK1) gene are associated with human chronic pancreatitis, but the underlying mechanisms remain unknown. We previously reported that mice lacking Spink3, the murine homologue of human SPINK1, die perinatally due to massive pancreatic acinar cell death, precluding investigation of the effects of SPINK1 deficiency. To circumvent perinatal lethality, we have developed a novel method to integrate human SPINK1 gene on the X chromosome using Cre-loxP technology and thus generated transgenic mice termed "X-SPINK1". Consistent with the fact that one of the two X chromosomes is randomly inactivated, X-SPINK1 mice exhibit mosaic pattern of SPINK1 expression. Crossing of X-SPINK1 mice with Spink3+/- mice rescued perinatal lethality, but the resulting Spink3-/-;XXSPINK1 mice developed spontaneous pancreatitis characterized by chronic inflammation and fibrosis. The results show that mice lacking a gene essential for cell survival can be rescued by expressing this gene on the X chromosome. The Spink3-/-;XXSPINK1 mice, in which this method has been applied to partially restore SPINK1 function, present a novel genetic model of chronic pancreatitis.

c-FLIP maintains tissue homeostasis by preventing apoptosis and programmed necrosis.

As a catalytically inactive homolog of caspase-8, a proapoptotic initiator caspase, c-FLIP blocks apoptosis by binding to and inhibiting caspase-8. The transcription factor nuclear factor κB (NF-κB) plays a pivotal role in maintaining the homeostasis of the intestine and the liver by preventing death receptor-induced apoptosis, and c-FLIP plays a role in the NF-κB-dependent protection of cells from death receptor signaling. Because c-Flip-deficient mice die in utero, we generated conditional c-Flip-deficient mice to investigate the contribution of c-FLIP to homeostasis of the intestine and the liver at developmental and postnatal stages. Intestinal epithelial cell (IEC)- or hepatocyte-specific deletion of c-Flip resulted in perinatal lethality as a result of the enhanced apoptosis and programmed necrosis of the IECs and the hepatocytes. Deficiency in the gene encoding tumor necrosis factor-α (TNF-α) receptor 1 (Tnfr1) partially rescued perinatal lethality and the development of colitis in IEC-specific c-Flip-deficient mice but did not rescue perinatal lethality in hepatocyte-specific c-Flip-deficient mice. Moreover, adult mice with interferon (IFN)-inducible deficiency in c-Flip died from hepatitis soon after depletion of c-FLIP. Pretreatment of IFN-inducible c-Flip-deficient mice with a mixture of neutralizing antibodies against TNF-α, Fas ligand (FasL), and TNF-related apoptosis-inducing ligand (TRAIL) prevented hepatitis. Together, these results suggest that c-FLIP controls the homeostasis of IECs and hepatocytes by preventing cell death induced by TNF-α, FasL, and TRAIL.

Interleukin-11 links oxidative stress and compensatory proliferation.

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.