論文

Signal transducer and activator of transcription 3 (STAT3) has been shown to mediate the anti-inflammatory effect of IL-10. Activated STAT3 suppresses LPS-induced IL-6, tumor necrosis factor-α and IL-12 gene expression in macrophages and dendritic cells. However, the mechanism of Toll-like receptor (TLR) signal suppression by STAT3 has not been clarified. In this study, we investigated the effect of constitutively activated STAT3 (STAT3C) on LPS-induced nuclear factor-κB (NF-κB) activation. The forced expression of STAT3C in HEK293/TLR4 cells, but neither wild-type STAT3 nor dominant-negative form of STAT3, suppressed LPS-TLR4-mediated NF-κB reporter activation. The over-expression of STAT3C did not affect the signal transduction of TLR4, such as the phosphorylation of inhibitory nuclear factor-κBα and mitogen-activated protein kinases and the DNA-binding activity of NF-κB. Thus, STAT3C could suppress the transcriptional and/or translational activity of NF-κB. To define the molecular mechanism, we searched STAT3C-binding proteins by using a proteomic approach and found that a novel RNA-binding protein, αCP-1, interacted with STAT3C. αCP-1 is a K-homology domain-containing RNA-binding protein with specificity for C-rich pyrimidine tracts. Such proteins play pivotal roles in a broad-spectrum of transcriptional and translational events. The over-expression of αCP-1 augmented the suppressive effect of STAT3C on NF-κB activation in HEK293/TLR4 cells. Furthermore, the forced expression of αCP-1 enhanced the antagonistic effect of IL-10 on IL-6 production in RAW264.7 cells, while small interfering RNA against αCP-1 reduced it. These data suggest that αCP-1 is involved in the STAT3-mediated suppression of NF-κB activity. © The Japanese Society for Immunology. 2007. All rights reserved.

Adipocyte differentiation is regulated by insulin and IGF-I, which transmit signals by activating their receptor tyrosine kinase. SH2-B is an adaptor protein containing pleckstrin homology and Src homology 2 (SH2) domains that have been implicated in insulin and IGF-I receptor signaling. In this study, we found a strong link between SH2-B levels and adipogenesis. The fat mass and expression of adipogenic genes including peroxisome proliferator-activated receptor γ (PPARγ) were reduced in white adipose tissue of SH2-B-/- mice. Reduced adipocyte differentiation of SH2-B-deficient mouse embryonic fibroblasts (MEFs) was observed in response to insulin and dexamethasone, whereas retroviral SH2-B overexpression enhanced differentiation of 3T3-L1 preadipocytes to adipocytes. SH2-B overexpression enhanced mRNA level of PPARγ in 3T3-L1 cells, whereas PPARγ levels were reduced in SH2-B-deficient MEFs in response to insulin. SH2-B-mediated up-regulation of PPARγ mRNA was blocked by a phosphatidylinositol 3-kinase inhibitor, but not by a MAPK kinase inhibitor. Insulin-induced Akt activation and the phosphorylation of forkhead transcription factor (FKHR/Foxo1), a negative regulator of PPARγ transcription, were up-regulated by SH2-B overexpression, but reduced in SH2-B-deficeint MEFs. These data indicate that SH2-B is a key regulator of adipogenesis both in vivo and in vitro by regulating the insulin/IGF-I receptor-Akt-Foxo1-PPARγ pathway. Copyright © 2007 by The Endocrine Society.

In the interferon-γ (IFNγ)-activated Janus Kinase (JAK)/signal transducer and activator of transcription 1 (STAT1) pathway, multiple steps of STAT1 dimerization are required prior to gene expression that produce antiviral molecules. By interpreting experimental results, an existing mathematical model suggested that only phosphorylated STAT1 dimers could translocate to the nucleus and activate gene transcription. In this paper, we examine the role of STAT1 dimerization steps by studying the dynamic behaviors of four alternative models. By analyzing several system properties at low input IFNγ signal including the steady-state antiviral molecule production, to the input, the delay of responses triggered by input, and the parameter sensitivity, we found that the mice JAK/STAT1 system identified by experiments (1) suppresses antiviral molecule production at low input signal, (2) has slow kinetics of antiviral molecule production and (3) has low parameter sensitivity of antiviral molecule production at steady state. We conclude that the observed structure of the JAK/STAT1 pathway is responsible for the robust system behavior. © 2007 Elsevier Ltd. All rights reserved.

Signal transducing adaptor protein-2 (STAP-2) is a recently identified adaptor protein that contains Pleckstrin and Src homology 2 (SH2)-like domains as well as a YXXQ motif in its C-terminal region. Our previous studies revealed that STAP-2 binds to signal transducer and activator of transcription 3 (STAT3) and STAT5, and regulates their signaling pathways. In the present study, we identified tyrosine-250 (Tyr250) in STAP-2 as a major site of phosphorylation by v-src and Jak2, using a phospho-specific antibody against STAP-2 phosphorylated at Tyr250. Mutational analyses revealed that Tyr250 was involved in the STAT3-enhancing activity of STAP-2. We further found that leukemia inhibitory factor (LIF) stimulated STAP-2 Tyr250 phosphorylation in 293T and Hep3B cells. Moreover, endogenous STAP-2 was phosphorylated at Tyr250 following LIF stimulation of murine M1 cell line. Taken together, our findings demonstrate that endogenous STAP-2 is phosphorylated at Tyr250 and that this phosphorylation is involved in its function. © 2007 Elsevier Inc. All rights reserved.

Purpose: The expression of suppressors of cytokine signaling 1 (SOCS1) and SOCS3 genes is dysregulated in several solid tumors, causing aberrant activation of cell growth and survival signaling pathways. In this study, we analyzed SOCS1 and SOCS3 gene expression in glioblastoma multiforme (GBM) and studied the role of each protein in GBM cell signaling and radiation resistance. Experimental Design: SOCS1 and SOCS3 gene expression was analyzed in 10 GBM cell lines by reverse transcription-PCR and Western blotting. SOCS3 expression was also studied in 12 primary GBM tissues by immunohistochemistry. The methylation status of the SOCS1 and SOCS3 loci was determined by methylation-specific PCR. Extracellular signal-regulated kinase (ERK)-mitogen-activated protein kinase (MAPK) activation in GBM cell lines overexpressing SOCS1 or lacking SOCS3 was determined by phosphorylated-specific Western blotting. Radiation responses in SOCS1-positive and SOCS3-deficient GBM cell lines and fibroblasts from wild-type and SOCS1 or SOCS3 knockout mice were studied in a clonogenic survival assay. Results: All GBM cell lines tested lacked SOCS1 expression, whereas GBM cell lines and primary GBM tumor samples constitutively expressed SOCS3. SOCS1 gene repression was linked to hypermethylation of the SOCS1 genetic locus in GBM cells. Reintroduction of SOCS1 or blocking SOCS3 expression sensitized cells to radiation and decreased the levels of activated ERK MAPKs in GBM cells. Conclusions: SOCS1 and SOCS3 are aberrantly expressed in GBM cell lines and primary tissues. Altered SOCS gene expression leads to increased cell signaling through the ERK-MAPK pathway and may play a role in disease pathogenesis by enhancing GBM radioresistance. © 2007 American Association for Cancer Research.

Signal transducer and activator of transcription 5 and 3 (Stat5 and Stat3) control pregnancy-mediated mammary development and involution-dependent remodeling, respectively. Suppressor of cytokine signaling 3 (Socs3) has been implicated in the modulation of both Stat3 and Stat5 activity. To explore the biology of Socs3 in mammary tissue, the gene was deleted using Cre-mediated recombination. Deletion of the Socs3 gene from mammary stem or early progenitor cells did not grossly alter pregnancy-mediated mammary development but resulted in impaired lactation due to attenuated proliferation. Loss of Socs3 from differentiated luminal cells did not interfere with glandular function during lactation, but resulted in accelerated tissue remodeling upon weaning. Loss of Socs3 led to enhanced and precocious Stat3 activation. Thus, Socs3 serves as a modulator of Stat3 activity to ensure controlled proliferation and apoptosis in pregnancy and involution, respectively.

Suppressor of cytokine signaling 3 (SOCS3) is an intracellular, ligand-induced negative feedback modulator of STAT3 activation that acts during inflammation. Here, we demonstrate that SOCS3 expression is important for normal retinal development in the perinatal period. STAT3 is highly activated in the late-embryonic retina, then downregulated at postnatal day 0 (P0), presumably by the depletion of upstream ligands. We found that SOCS3 was required after P0 to shut down the residual STAT3 activation; this loss of activated STAT3 leads to Rhodopsin expression and rod photoreceptor cell differentiation. SOCS3 deficiency failed to terminate STAT3 activation, thereby delaying expression of Rhodopsin and its upstream transcription factor, crx. Development subsequently continued, but its course was temporally erratic, probably because of faulty compensation. Interestingly, SOCS3 protein expression was first detected postnatally, after STAT3 activation was mostly downregulated. It initially appeared in some of the presumptive photoreceptor cells and gradually spread. SOCS3 mRNA level was constant from the late-embryonic to early-postnatal period. Post-transcriptional inhibition of SOCS3 protein expression maintains a high STAT3 activation during late embryogenesis, and after P0, releasing from the inhibition promptly terminates STAT3 activation. Thus, SOCS3 can act as a temporal fine-tuner of STAT3 activation during photoreceptor cell differentiation. © 2006 Elsevier Inc. All rights reserved.

Inflammation associates with insulin resistance, which dysregulates nutrient homeostasis and leads to diabetes. The suppressor of cytokine signaling 3 (SOCS3), which is induced by pro-inflammatory cytokines, such as TNFα and IL-6, has been implicated in inflammation-mediated insulin resistance in the liver and adipocytes. However, no genetic evidence has been provided for the involvement of SOCS3 on insulin resistance. Here, we generated hepatocyte-specific SOCS3-deficient (L-SOCS3 cKO) mice and examined insulin sensitivity. Being consistent with a previous idea, the loss of SOCS3 in the liver apparently improved insulin sensitivity. However, unexpectedly, L-SOCS3 cKO mice exhibited obesity and systemic insulin resistance with age. Insulin signaling was rather suppressed in muscles, suggesting that deletion of the SOCS3 gene in the liver modulates insulin sensitivity in other organs. Anti-inflammatory reagent, sodium salicylate, partial improved insulin resistance of aged L-SOCS3 cKO mice, suggesting that enhanced inflammatory status is associated with the phenotype of these mice. STAT3 was hyperactivated and acute-phase proteins were elevated in L-SOCS3 cKO mice liver, which were reduced by sodium salicylate treatment. We conclude that hepatic SOCS3 is a mediator of insulin resistance in the liver; however, lack of SOCS3 in the liver promotes systemic insulin resistance by mimicking chronic inflammation. © 2007 The Authors Journal compilation © 2007 by the Molecular Biology Society of Japan/Blackwell Publishing Ltd.

T helper 2 cytokines, including interleukin (IL)-4, IL-5, and IL-13, play an important role in allergic immune disorders, such as bronchial asthma. These cytokines regulate diverse biological functions by binding to receptors at the cell surface to activate complex signal transduction pathways, including the Janus kinase-signal transducer and activator of transcription (JAK-STAT) and the Ras-extracellular signal-regulated kinase (ERK) signaling pathways. The suppressor of cytokine signaling (SOCS) family proteins has been shown to regulate the JAK-STAT pathway, and the Sprouty-related EVH1-domain-containing protein (SPRED) family proteins regulate the Ras-ERK pathway. SOCS3 and SOCS5 are predominantly expressed in Th2 and Th1 cells, respectively, and they reciprocally inhibit the Th1 and Th2 differentiation processes. SOCS3 also has a role in Th3 differentiation. SPRED-1 is expressed in hematopoietic cells, including eosinophils, and negatively controls the eosinophil numbers and functions by modulating IL-5 signaling. Here, we discuss the role of SOCS and SPRED proteins in allergic asthma and explore the potential of these proteins as targets for therapeutic strategies in allergic asthma. © 2007 Bentham Science Publishers Ltd.

Sprouty genes encode cytoplasmic membrane-associated proteins that inhibit receptor tyrosine kinase signaling. Four orthologs of Drosophila Sprouty (dSpry) (Sprouty1-4) have been identified in mammals. Physiological function of Sprouty1 and Sprouty2 has been investigated using gene targeting approaches, however to date detailed examination of Sprouty4 knockout (KO) mice has not been reported. In this study, Sprouty4 KO mice were generated and characterized. Although a significant fraction of Sprouty4 KO mice died shortly after birth due to mandible defects, the remainder were viable and fertile. Growth retardation was observed for most Sprouty4-deficient mice, with nearly all Sprouty4 KO mice having polysyndactyly. ERK activation was sustained in Sprouty4 KO mouse embryonic fibroblasts (MEFs) in response to FGF, but not to EGF. Sprouty2 and Sprouty4 double KO (DKO) mice were embryonic lethal and showed severe defects in craniofacial, limb, and lung morphogenesis. These findings suggest both redundant and non-redundant functions for Sprouty2 and Sprouty4 on embryonic development and FGF signaling. © 2006 Elsevier Inc. All rights reserved.

The transcription factor STAT3 is activated by interleukin-6-related cytokines and has been implicated as an oncogene; it promotes cell proliferation and is anti-apoptotic. However, in some cases, STAT3 has been shown to be pro-apoptotic, especially in mammary epithelial cells. In this report, we generated SOCS3-deficient murine embryonic fibroblasts (MEFs), in which STAT3 activation is extremely enhanced and prolonged. We found that LIF induces caspase-3 activation and apoptosis of SOCS3-/- MEFs. Exogenous expression of the dominant negative form of STAT3 but not STAT1 suppressed LIF-induced apoptosis of SOCS3-/- MEFs, indicating that STAT3 plays a critical role in apoptosis induction. As shown in mammary gland epithelial cells, expression of the phosphatidylinositol 3-kinase regulatory subunits p50α and p55α was induced in response to LIF in SOCS3-/- MEFs but not in wild-type MEFs, and Akt/protein kinase B activity was substantially reduced in SOCS3-/- MEFs. Furthermore, we found that some of the STAT3 target genes related to apoptosis and proliferation, such as Bcl-2 and cyclin D1, were repressed upon LIF treatment in SOCS3-/- cells. Not only the up-regulation of p50α and p55α but also the repression of cyclin D1 and Bcl-2 in SOCS3-/- MEFs was inhibited by dominant negative STAT3. These data suggest that prolonged activation of STAT3 could induce apoptosis/growth arrest rather than anti-apoptosis and proliferation in certain cases, and SOCS3 is a critical regulator of this balance. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.

BACKGROUND - Little is known about innate immune mechanisms within the cardiac myocyte that determine susceptibility to enterovirus infection, an important cause of myocarditis and subsequent heart failure. Although interferon (IFN) generally plays a key role in innate immunity, ablation of IFN receptors has little or no effect on acute coxsackievirus B3 infection in the heart. Interestingly, gp130-cytokine-mediated stimulation of neonatal ventricular myocytes has a cytoprotective effect against virus infection in culture that can be inhibited by suppressors of cytokine signaling (SOCS)-3, a physiological inhibitor of gp130 signaling that does not affect IFN signaling. Therefore, we hypothesized that inhibition of gp130 signaling by SOCS3 would change cardiac myocyte susceptibility to virus infection without affecting IFN signaling. METHODS AND RESULTS - We generated cardiac-specific SOCS3 transgenic mice. Despite an intact IFN-mediated antiviral response in adult transgenic myocytes, there was a marked increase in susceptibility to viral infection in the SOCS3 transgenic mouse hearts. This indicated the presence of IFN-independent innate defense mechanisms within the cardiac myocyte. Subsequently, we demonstrated that cardiac-specific gp130-knockout mice also had increased susceptibility to viral infection. Furthermore, we demonstrated that the gp130-mediated increase in survival of infected myocytes occurred through a signal transducers and activators of transcription-3-dependent mechanism that did not affect viral replication. This was accompanied by a persistent expression of full-length dystrophin after coxsackievirus B3 infection. In addition, we found that both SOCS3 transgenic and gp130-deficient mice had a decrease in α-sarcoglycan. CONCLUSIONS - SOCS3-mediated regulation of gp130 signaling can affect susceptibility to viral infection in the heart. Increased cardiac cell survival through gp130-signal transducers and activators of transcription-3 signaling appears to play an important role in preserving nondividing cardiac myocytes until specific immune responses begin to clear the virus. © 2006 American Heart Association, Inc.

Recent lines of evidence have demonstrated that IL-27, a newly identified IL-12-related cytokine, has two apparently conflicting roles in immune responses: one as an initiator of Th1 responses and the other as an attenuator of inflammatory cytokine production. Although the BL-27-mediated Th1 initiation mechanism has been elucidated, little is known about the molecular basis for the suppression of cytokine production. In the present study, we demonstrated that IL-27 suppressed the production of various proinflammatory cytokines by fully activated CD4+ T cells while it had no effect on the cytokine production by CD4+ T cells at early phases of activation. IL-27 also suppressed IL-17 production by activated CD4+ T cells, thereby counteracting IL-23, another IL-12-related cytokine with proinflammatory effects. In fully activated CD4+ T cells, STAT3 was preferentially activated by IL-27 stimulation, whereas both STAT1 and 3 were activated by IL-27 in early activated CD4+ T cells. Lack of STAT3 in fully activated cells impaired the suppressive effects of IL-27. These data indicated that the preferential activation of STAT3 in fully activated CD4+ T cells plays an important role in the cytokine suppression by IL-27/WSX-1. Copyright © 2006 by The American Association of Immunologists, Inc.

Aberrant activation of the Ras/Raf-1/extracellular-regulated kinase (ERK) pathway has been shown to be involved in the progression of human hepatocellular carcinoma (HCC). However, the mechanism of dysregulation of ERK activation is poorly understood. Recently, we identified Sprouty-related protein with Ena/vasodilator-stimulated phosphoprotein homology-1 domain (Spred) as a physiological inhibitor of the Ras/Raf-1/ERK pathway. In this study, we found that the expression levels of Spred-1 and -2 in human HCC tissue were frequently decreased, comparing with those in adjacent non-tumorous tissue. Moreover, Spred expression levels in HCC tissue were inversely correlated with the incidence of tumor invasion and metastasis. Forced expression of Spred-1 inhibited HCC cell proliferation in vitro and in vivo, which was associated with reduced ERK activation. Spred-1 overexpression also reduced the secretion of matrix metalloproteinase-9 (MMP-9) and MMP-2, which play important roles in tumor invasion and metastasis. In addition, Spred-1 inhibited growth factor-mediated HCC cell motility. These data indicate that the reduction of Spred expression in HCC is one of the causes of the acquisition of malignant features. Thus, Spred could be not only a novel prognostic factor but also a new therapeutic target for human HCC. © 2006 Nature Publishing Group. All rights reserved.

Accumulation of unfolded proteins induces endoplasmic reticulum (ER) stress. Excessive and prolonged stresses lead cells to apoptosis. However, the precise molecular mechanisms of ER stress-induced apoptosis have not been fully elucidated. We investigated the involvement of the apoptosome in ER stress-induced cell death pathway using mouse embryonic fibroblasts (MEFs) and mice deficient for Apaf-1. Apaf-1-deficient MEFs showed ore resistance to ER stress-inducing reagents as compared with wild type cells. Despite comparable induction of ER stress in both wild type and Apaf-1-deficient cells, activation of caspase-3 was only observed in wild type, but not Apaf-1-deficient, MEFs. Under ER stress conditions, BAX translocated to mitochondria and cytochrome c was released from mitochondria. We also demonstrated that caspase-12 was processed downstream of Apaf-1 and caspase-3, and neither overexpression nor knockdown of caspase-12 affected susceptibility of the cells to ER stress-induced cell death. Furthermore, in the kidneys of Apaf-1-deficient mice, apoptosis induced by in vivo administration of tunicamycin was remarkably suppressed as compared with wild type mice. These data collectively demonstrated that Apaf-1 and the mitochondrial pathway of apoptosis play significant roles in ER stress-induced apoptosis.

Studies have focused on the events that influence the development of interleukin 17 (IL-17)-producing T helper cells (TH-17 cells) associated with autoimmunity, such as experimental autoimmune encephalitis, but relatively little is known about the cytokines that antagonize TH-17 cell effector responses. Here we show that IL-27 receptor-deficient mice chronically infected with Toxoplasma gondii developed severe neuroinflammation that was CD4+ T cell dependent and was associated with a prominent IL-17 response. In vitro, treatment of naive primary T cells with IL-27 suppressed the development TH-17 cells induced by IL-6 and transforming growth factor-β, which was dependent on the intracellular signaling molecule STAT1 but was independent of inhibition of IL-6 signaling mediated by the suppressor protein SOCS3. Thus IL-27, a potent inhibitor of TH-17 cell development, may be a useful target for treating inflammatory diseases mediated by these cells.

TGF-β1 is a well-known immunosuppressive cytokine; however, little is known of the effect of TGF-β1 on antigen-presenting cells (APCs). In this report, we investigated the molecular mechanisms of the suppressive effects of TGF-β1 on APCs including dendritic cells and macrophages. Although TGF-β1 did not greatly affect the activation of APCs, as assessed by the induction of IL-12 or the upregulation of CD40 in response to LPS, it strongly inhibited IFN-γ-induced nitric oxide (NO) production from macrophages and dendritic cells. Using murine macrophage-like cell line RAW 264.7, we demonstrated that TGF-β1 not only reduced the inducible NO synthase (iNOS) protein stability but also suppressed the iNOS gene transcription. We also found that TGF-β1 directly inhibited IFN-γ-induced STAT1 activation by reducing STAT1 tyrosine phosphorylation. The IFN-γ Type I receptor (IFNGR1) was found to be associated with the TGF-β1 Type I receptor (TGF-βRI) and was phosphorylated by the TGF-βRI. Reduced activation of STAT1 by TGF-β1 was abrogated by the mutation in the IFNGR1 in which the serine residues of potential sites of phosphorylation by TGF-βRI were replaced by alanine residues. Thus, multiple mechanisms are present for the TGF-β1-mediated reduction of iNOS production, and we propose a novel mechanism for regulating inflammatory cytokine by an anti-inflammatory cytokine, TGF-β1; i.e. suppression of IFN-γ-induced STAT1 activation by an association of the IFNGR1 with the TGF-βRI. © 2006 The Authors Journal compilation © 2006 by the Molecular Biology Society of Japan/Blackwell Publishing Ltd.

Suppressor of cytokine signaling-3 (Socs-3) negatively regulates the action of various cytokines, as well as the metabolic hormones leptin and insulin. Mice with haploinsufficiency of Socs-3, or those with neuronal deletion of Socs-3, are lean and more leptin and insulin sensitive. To examine the role of Socs-3 within specific neurons critical to energy balance, we created mice with selective deletion of Socs-3 within pro-opiomelanocortin (POMC)-expressing cells. These mice had enhanced leptin sensitivity, measured by weight loss and food intake after leptin infusion. On chow diet, glucose homeostasis was improved despite normal weight gain. On a high-fat diet, the rate of weight gain was reduced, due to increased energy expenditure rather than decreased food intake; glucose homeostasis and insulin sensitivity were substantially improved. These studies demonstrate that Socs-3 within POMC neurons regulates leptin sensitivity and glucose homeostasis, and plays a key role in linking high-fat diet to disordered metabolism. © 2006 Elsevier Inc. All rights reserved.

Background & Aims: A recent study has suggested that the methylation silencing of the suppressor of cytokine signaling-3 (SOCS3), a negative regulator of interleukin-6-related cytokines, could be involved in hepatocellular carcinoma (HCC). However, the roles of SOCS3 in hepatocellular carcinogenesis and hepatitis have not been established. We investigated the effect of deleting the SOCS3 gene on the development of hepatitis and HCC in hepatitis C virus-infected patients and mouse models. Methods: The expression of SOCS genes in HCC and non-HCC regions of patient samples was determined by real-time reverse-transcription polymerase chain reaction and immunoblotting. The conditional knockout approach in mice was used to determine the hepatocyte-specific roles of SOCS3. To generate a liver-specific deletion, floxed SOCS3 (SOCS3fl/fl) mice were crossed with albumin-Cre transgenic mice. Hepatitis and HCC were induced by administering concanavalin A and diethylnitrosamine, respectively. Results: SOCS3 expression was reduced in the HCC regions compared with the non-HCC regions. Carcinogen-induced hepatic tumor development was enhanced by deletion of the SOCS3 gene, which was associated with higher levels of the targets of signal transducers and activators of transcription (ie, B-cell lymphoma-XL, B-cell lymphoma-2, C-myelocytomatosis, cyclin D1, and vascular endothelial growth factor). In the concanavalin A-mediated hepatitis model, deletion of the SOCS3 gene in the hepatocytes protected against liver injury through suppression of interferon-γ signaling and induction of the antiapoptotic protein Bcl-XL. Conclusions: Deletion of the SOCS3 gene in hepatocytes promotes the activation of STAT3, resistance to apoptosis, and an acceleration of proliferation, resulting in enhanced hepatitis-induced hepatocarcinogenesis. © 2006 American Gastroenterological Association Institute.