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1.
Proc Natl Acad Sci U S A ; 118(12)2021 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-33798093

RESUMO

The c-Jun N-terminal kinase (JNK) signaling pathway mediates adaptation to stress signals and has been associated with cell death, cell proliferation, and malignant transformation in the liver. However, up to now, its function was experimentally studied mainly in young mice. By generating mice with combined conditional ablation of Jnk1 and Jnk2 in liver parenchymal cells (LPCs) (JNK1/2LPC-KO mice; KO, knockout), we unraveled a function of the JNK pathway in the regulation of liver homeostasis during aging. Aging JNK1/2LPC-KO mice spontaneously developed large biliary cysts that originated from the biliary cell compartment. Mechanistically, we could show that cyst formation in livers of JNK1/2LPC-KO mice was dependent on receptor-interacting protein kinase 1 (RIPK1), a known regulator of cell survival, apoptosis, and necroptosis. In line with this, we showed that RIPK1 was overexpressed in the human cyst epithelium of a subset of patients with polycystic liver disease. Collectively, these data reveal a functional interaction between JNK signaling and RIPK1 in age-related progressive cyst development. Thus, they provide a functional linkage between stress adaptation and programmed cell death (PCD) in the maintenance of liver homeostasis during aging.


Assuntos
Envelhecimento/metabolismo , Doenças dos Ductos Biliares/etiologia , Doenças dos Ductos Biliares/metabolismo , Caspase 8/metabolismo , Cistos/etiologia , Cistos/metabolismo , Sistema de Sinalização das MAP Quinases , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Animais , Apoptose , Biópsia , Modelos Animais de Doenças , Suscetibilidade a Doenças , Imuno-Histoquímica , Imunofenotipagem , Hepatopatias/etiologia , Hepatopatias/metabolismo , Camundongos , Proteína Quinase 8 Ativada por Mitógeno/deficiência , Necroptose
2.
Hepatology ; 64(4): 1217-31, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27396433

RESUMO

UNLABELLED: The IκB-Kinase (IKK) complex-consisting of the catalytic subunits, IKKα and IKKß, as well as the regulatory subunit, NEMO-mediates activation of the nuclear factor κB (NF-κB) pathway, but previous studies suggested the existence of NF-κB-independent functions of IKK subunits with potential impact on liver physiology and disease. Programmed cell death is a crucial factor in the progression of liver diseases, and receptor-interacting kinases (RIPKs) exerts strategic control over multiple pathways involved in regulating novel programmed cell-death pathways and inflammation. We hypothesized that RIPKs might be unrecognized targets of the catalytic IKK-complex subunits, thereby regulating hepatocarcinogenesis and cholestasis. In this present study, mice with specific genetic inhibition of catalytic IKK activity in liver parenchymal cells (LPCs; IKKα/ß(LPC-KO) ) were intercrossed with RIPK1(LPC-KO) or RIPK3(-/-) mice to examine whether RIPK1 or RIPK3 might be downstream targets of IKKs. Moreover, we performed in vivo phospho-proteome analyses and in vitro kinase assays, mass spectrometry, and mutagenesis experiments. These analyses revealed that IKKα and IKKß-in addition to their known function in NF-κB activation-directly phosphorylate RIPK1 at distinct regions of the protein, thereby regulating cell viability. Loss of this IKKα/ß-dependent RIPK1 phosphorylation in LPCs inhibits compensatory proliferation of hepatocytes and intrahepatic biliary cells, thus impeding HCC development, but promoting biliary cell paucity and lethal cholestasis. CONCLUSIONS: IKK-complex subunits transmit a previously unrecognized signal through RIPK1, which is fundamental for the long-term consequences of chronic hepatic inflammation and might have potential implications for future pharmacological strategies against cholestatic liver disease and cancer. (Hepatology 2016;64:1217-1231).


Assuntos
Homeostase , Quinase I-kappa B/fisiologia , Neoplasias Hepáticas/etiologia , Ubiquitina-Proteína Ligases/metabolismo , Animais , Ductos Biliares Intra-Hepáticos , Carcinogênese , Masculino , Camundongos , Fosforilação
3.
Clin Sci (Lond) ; 131(15): 1971-1987, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28646120

RESUMO

BACKGROUND: Dysregulation of miRNAs has been described in tissue and serum from patients with acute and chronic liver diseases. However, only little information on the role of miR-223 in the pathophysiology of acute liver failure (ALF) and liver cirrhosis is available. METHODS: We analysed cell and tissue specific expression levels as well as serum concentrations of miR-223 in mouse models of acute (hepatic ischaemia and reperfusion, single CCl4 injection) and chronic (repetitive CCl4 injection, bile duct ligation (BDL)) liver diseases. Results were validated in patients and correlated with clinical data. The specific hepatic role of miR-223 was analysed by using miR-223-/- mice in these models. RESULTS: miR-223 expression was significantly dysregulated in livers from mice after induction of acute liver injury and liver fibrosis as well as in liver samples from patients with ALF or liver cirrhosis. In acute and chronic models, hepatic miR-223 up-regulation was restricted to hepatocytes and correlated with degree of liver injury and hepatic cell death. Moreover, elevated miR-223 expression was reflected by significantly higher serum levels of miR-223 during acute liver injury. However, functional in vitro and in vivo experiments revealed no differences in the degree of liver cell death and liver fibrosis as miR-223-/- mice behaved identical with wild-type (wt) mice in all tested models. CONCLUSION: miR-223 represents a promising diagnostic marker in a panel of serum markers of liver injury. Together with previously published data, our results highlight that the role of miR-223 in the pathophysiology of the liver is complex and needs further analysis.


Assuntos
Cirrose Hepática/metabolismo , Falência Hepática/metabolismo , MicroRNAs/metabolismo , Doença Aguda , Animais , Biomarcadores/metabolismo , Doença Crônica , Feminino , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/genética , Falência Hepática/diagnóstico , Falência Hepática/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética
4.
Liver Int ; 35(4): 1172-84, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25039534

RESUMO

BACKGROUND & AIMS: Serum concentrations of miR-122 were proposed as a marker for various inflammatory diseases, but the mechanisms driving alterations in miR-122 serum levels are unknown. METHODS: We analysed miR-122 serum levels and hepatic miR-122 expression in mice after hepatic ischaemia and reperfusion (I/R) injury. These data were compared with data from mice after caecal pole ligation and puncture (CLP) procedure. To translate these data into the human, we analysed miR-122 serum concentrations in a cohort of 223 patients with critical illness and 57 patients with cirrhosis. RESULTS: We detected strongly elevated levels of miR-122 in mice after hepatic I/R injury. miR-122-concentrations correlated with the degree of liver damage according to AST/ALT and were associated with the presence of hepatic cell death detected by TUNEL staining. miR-122 levels were elevated in the cellular supernatants in an in vitro model of hepatocyte injury, supporting the hypothesis that the passive release of miR-122 represents a surrogate for hepatocyte death in liver injury. Moreover, miR-122 levels were almost normal in patients with cirrhosis without ongoing liver damage, but were elevated when liver injury was present. In contrast to previous assumptions, miR-122-concentrations were independent of the presence of infection/sepsis in mice or human patients. miR-122 levels did not correlate with disease severity or mortality in critically ill patients. In contrast, serum miR-122 levels strictly correlated with the presence of hepatic injury in these patients. CONCLUSION: In mice and humans, miR-122 levels represent an independent and potent marker of ongoing liver injury and hepatic cell death regardless of the underlying disease.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/sangue , Cirrose Hepática/sangue , MicroRNAs/sangue , Traumatismo por Reperfusão/sangue , Sepse/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Estudos de Casos e Controles , Morte Celular , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/patologia , Estado Terminal , Modelos Animais de Doenças , Feminino , Marcadores Genéticos , Humanos , Fígado/patologia , Cirrose Hepática/diagnóstico , Cirrose Hepática/genética , Cirrose Hepática/patologia , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologia , Sepse/diagnóstico , Sepse/genética , Sepse/patologia , Regulação para Cima , Adulto Jovem
5.
Hepatology ; 53(1): 209-18, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20890893

RESUMO

UNLABELLED: Liver fibrosis is orchestrated by a complex network of signaling pathways regulating the deposition of extracellular matrix proteins during fibrogenesis. MicroRNAs (miRNAs) represent a family of small noncoding RNAs controlling translation and transcription of many genes. Recently, miRNAs have been suggested to crucially modulate cellular processes in the liver such as hepatocarcinogenesis. However, their role in liver fibrosis is not well understood. We systematically analyzed the regulation of miRNAs in a mouse model of carbon tetrachloride-induced hepatic fibrogenesis (CCl(4) ) by gene array analysis, which revealed a panel of miRNA that were specifically regulated in livers of mice undergoing hepatic fibrosis. Within those, all three members of the miR-29-family were significantly down-regulated in livers of CCl(4) -treated mice as well as in mice that underwent bile duct ligation. Specific regulation of miR-29 members in murine fibrosis models correlated with lower expression of miR-29 in livers from patients with advanced liver fibrosis. Moreover, patients with advanced liver cirrhosis showed significantly lower levels of miR-29a in their serum when compared with healthy controls or patients with early fibrosis. On a cellular level, down-regulation of miR-29 in murine hepatic stellate cells (HSCs) was mediated by transforming growth factor beta (TGF-ß) as well as inflammatory signals, namely, lipopolysaccharide (LPS) and nuclear factor kappa B (NF-κB). Furthermore, overexpression of miR-29b in murine HSC resulted in down-regulation of collagen expression. CONCLUSION: Our data indicate that miR-29 mediates the regulation of liver fibrosis and is part of a signaling nexus involving TGF-ß- and NF-κB-dependent down-regulation of miR-29 family members in HSC with subsequent up-regulation of extracellular matrix genes. Thus they may represent targets for novel therapeutic strategies against hepatic fibrogenesis and also might evolve as biomarkers in the diagnosis of liver fibrosis.


Assuntos
Cirrose Hepática/genética , MicroRNAs/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Ductos Biliares/fisiologia , Intoxicação por Tetracloreto de Carbono/fisiopatologia , Modelos Animais de Doenças , Regulação para Baixo , Matriz Extracelular/genética , Feminino , Células Estreladas do Fígado/metabolismo , Humanos , Ligadura , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , NF-kappa B/fisiologia , Fator de Crescimento Transformador beta/fisiologia
6.
Cell Mol Gastroenterol Hepatol ; 11(2): 327-347, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32896623

RESUMO

BACKGROUND & AIMS: Macrophages are key regulators of inflammation and cancer promotion in the liver, and their recruitment and activation is linked to chemokine receptor signaling. However, the exact roles of the chemokine receptors CCR2 and CCR5 for macrophage functions in the liver is obscure. METHODS: To study CCR2 and CCR5 in inflammatory liver injury, we used mice with a hepatocyte-specific knock-out of the nuclear factor κB (NF-κB) essential modulator (NEMO), termed NEMOLPC-KO mice, and generated NEMOLPC-KOCcr2-/- and NEMOLPC-KOCcr5-/- mice. NEMOLPC-KO mice develop hepatitis and fibrosis after two and liver tumors after six months. RESULTS: We found that both CCR2 and CCR5 deficiency led to reduced fibrosis, while CCR5 deficiency increased steatosis and tumor burden in NEMOLPC-KO mice. CCR2 was required for recruitment of hepatic macrophages, whereas CCR5 promoted stellate cell activation. The reduction of monocytes and macrophages by either anti-Gr1 antibody or clodronate-loaded liposomes (CLL), but not of CD8+ T cells or NK cells, significantly aggravated liver injury in NEMOLPC-KO mice and was further increased in NEMOLPC-KOCcr5-/- mice. CLL-induced liver injury was dampened by the adoptive transfer of ex vivo generated macrophages, whereas the adoptive transfer of control CD115+ immature monocytes or B cells did not reduce liver injury. CONCLUSIONS: Although CCR2 and CCR5 principally promote liver fibrosis, they exert differential functions on hepatic macrophages during liver disease progression in NEMOLPC-KO mice. While CCR2 controls the recruitment of monocytes to injured livers, CCR5-dependent functions of liver macrophages limit hepatic injury, thereby reducing steatosis and hepatocarcinogenesis.


Assuntos
Hepatite/imunologia , Cirrose Hepática/imunologia , Neoplasias Hepáticas/imunologia , Macrófagos/imunologia , Receptores CCR2/metabolismo , Receptores CCR5/metabolismo , Animais , Carcinogênese/imunologia , Carcinogênese/patologia , Células Cultivadas , Modelos Animais de Doenças , Progressão da Doença , Hepatite/patologia , Hepatócitos/imunologia , Hepatócitos/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Fígado/citologia , Fígado/imunologia , Fígado/patologia , Cirrose Hepática/patologia , Neoplasias Hepáticas/patologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Cultura Primária de Células , Receptores CCR2/genética , Receptores CCR5/genética
7.
Front Oncol ; 11: 646883, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33869041

RESUMO

BACKGROUND: Immune checkpoint inhibitors (ICIs) have led to a paradigm shift in cancer therapy, improving outcomes in the treatment of various malignancies. However, not all patients benefit to the same extend from ICI. Reliable tools to predict treatment response and outcome are missing. Soluble urokinase plasminogen activator receptor (suPAR) is a marker of immune activation, whose levels are prognostic in various cancers. We evaluated circulating suPAR levels as a novel predictive and prognostic biomarker in patients receiving ICI therapy for solid tumors. METHODS: A total of n = 87 patients receiving ICI therapy for different solid malignancies as well as 32 healthy controls were included into this study. Serum levels of suPAR were measured by ELISA prior to and sequentially at two time points during ICI therapy. RESULTS: Baseline suPAR serum levels were significantly higher in solid tumor patients compared to healthy controls. Importantly, patients with low suPAR levels both before or during ICI treatment were more likely to have a favorable response to treatment at three and six months, respectively. This finding was confirmed by multivariate binary logistic regression analysis including several clinicopathological parameters. Moreover, circulating suPAR levels before and during therapy were an independent prognostic factor for overall survival (OS). As such, patients with initial suPAR levels above our ideal prognostic cut-off value (4.86 ng/ml) had a median OS of only 160 days compared to 705 days for patients with suPAR levels below this cut-off value. Finally, low baseline suPAR levels identified a subgroup of patients who experienced ICI-related side effects which in turn were associated with favorable treatment response and outcome. CONCLUSION: Our data suggest that measurements of suPAR serum levels are a previously unknown, easily accessible tool to predict individual treatment response and outcome to ICI therapy. Circulating suPAR might therefore be implemented into stratification algorithms to identify the ideal candidates for ICI treatment.

8.
PLoS One ; 15(9): e0239386, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32960907

RESUMO

While tumor resection and liver transplantation (LT) represent potentially curative therapeutic options for patients with early-stage hepatocellular carcinoma (HCC), the identification of the ideal surgical candidates has remained challenging. Just recently, miRNA-193a-5p was described as a tumor suppressor in murine and human HCC but only little is known about circulating miRNA-193a-5p in HCC patients. Here, we evaluated serum levels of miR-193a-5p by qPCR in 41 HCC patients undergoing tumor resection (n = 33) or LT (n = 8) and 20 controls. Circulating relative miR-193a-5p levels were significantly elevated in HCC patients compared to healthy controls. While relative miR-193a-5p levels were comparable between patients of different underlying disease etiology and tumor size, high relative miR-193a-5p levels were predictive for the patients' postoperative outcome, which was confirmed in uni- and multivariate Cox-regression analysis. As such, HCC patients with a preoperative relative miR-193a-5p level above the ideal cut-off value (3.57) had a median overall survival (OS) of only 451 days compared to 1158 days in patients with a relative miR-193a-5p level below this cut-off value. Our data support a novel function of miR-193a-5p as a biomarker in early-stage HCC patients that might help to identify the best surgical candidates in terms of postoperative outcome.


Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , MicroRNAs/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidade , Estudos de Casos e Controles , Feminino , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Curva ROC , Taxa de Sobrevida , Regulação para Cima
9.
Cancers (Basel) ; 11(7)2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31319593

RESUMO

The IκBKinase (IKK) complex represents a central signaling nexus in the TNF-dependent activation of the pro-inflammatory NF-κB pathway. However, recent studies suggested that the distinct IKK subunits (IKK, IKK, and NEMO) might withhold additional NF-κB-independent functions in inflammation and cancer. Here, we generated mice lacking all three IKK subunits in liver parenchymal cells (LPC) (IKK//NEMOLPC-KO) and compared their phenotype with mice lacking both catalytic subunits (IKK/LPC-KO), allowing to functionally dissect putative I-κB-Kinase-independent functions of the regulatory subunit NEMO. We show that the additional deletion of NEMO rescues IKK/LPC-KO mice from lethal cholestasis and biliary ductopenia by triggering LPC apoptosis and inducing a strong compensatory proliferation of LPC including cholangiocytes. Beyond this beneficial effect, we show that increased hepatocyte cell-death and compensatory proliferation inhibit the activation of LPC-necroptosis but trigger spontaneous hepatocarcinogenesis in IKK//NEMOLPC-KO mice. Collectively, our data show that free NEMO molecules unbound to the catalytic IKK subunits control LPC programmed cell death pathways and proliferation, cholestasis and hepatocarcinogenesis independently of an IKK-related function. These findings support the idea of different functional levels at which NEMO controls inflammation and cancer in the liver.

10.
Cancer Cell ; 32(3): 342-359.e10, 2017 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-28898696

RESUMO

Concomitant hepatocyte apoptosis and regeneration is a hallmark of chronic liver diseases (CLDs) predisposing to hepatocellular carcinoma (HCC). Here, we mechanistically link caspase-8-dependent apoptosis to HCC development via proliferation- and replication-associated DNA damage. Proliferation-associated replication stress, DNA damage, and genetic instability are detectable in CLDs before any neoplastic changes occur. Accumulated levels of hepatocyte apoptosis determine and predict subsequent hepatocarcinogenesis. Proliferation-associated DNA damage is sensed by a complex comprising caspase-8, FADD, c-FLIP, and a kinase-dependent function of RIPK1. This platform requires a non-apoptotic function of caspase-8, but no caspase-3 or caspase-8 cleavage. It may represent a DNA damage-sensing mechanism in hepatocytes that can act via JNK and subsequent phosphorylation of the histone variant H2AX.


Assuntos
Carcinogênese/metabolismo , Carcinogênese/patologia , Caspase 8/metabolismo , Dano ao DNA , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/patologia , Animais , Apoptose , Carcinoma Hepatocelular/patologia , Proliferação de Células , Senescência Celular , Doença Crônica , Cruzamentos Genéticos , Reparo do DNA , Proteína de Domínio de Morte Associada a Fas/metabolismo , Feminino , Instabilidade Genômica , Hepatectomia , Hepatócitos/patologia , Histonas/metabolismo , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Fígado/metabolismo , Fígado/patologia , Regeneração Hepática , Masculino , Camundongos , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Fosforilação , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Fatores de Risco
11.
Sci Signal ; 9(442): ra85, 2016 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-27555662

RESUMO

Nuclear factor κB (NF-κB) is a master regulator of inflammation and cell death. Whereas most of the activity of NF-κB is regulated through the inhibitor of κB (IκB) kinase (IKK)-dependent degradation of IκB, IKK also phosphorylates subunits of NF-κB. We investigated the contribution of the phosphorylation of the NF-κB subunit p65 at the IKK phosphorylation site serine 536 (Ser(536)) in humans, which is thought to be required for the activation and nuclear translocation of NF-κB. Through experiments with knock-in mice (S534A mice) expressing a mutant p65 with an alanine-to-serine substitution at position 534 (the murine homolog of human Ser(536)), we observed increased expression of NF-κB-dependent genes after injection of mice with the inflammatory stimulus lipopolysaccharide (LPS) or exposure to gamma irradiation, and the enhanced gene expression was most pronounced at late time points. Compared to wild-type mice, S534A mice displayed increased mortality after injection with LPS. Increased NF-κB signaling in the S534A mice was at least in part explained by the increased stability of the S534A p65 protein compared to that of the Ser(534)-phosphorylated wild-type protein. Together, our results suggest that Ser(534) phosphorylation of p65 in mice (and, by extension, Ser(536) phosphorylation of human p65) is not required for its nuclear translocation, but instead inhibits NF-κB signaling to prevent deleterious inflammation.


Assuntos
Transdução de Sinais , Fator de Transcrição RelA/metabolismo , Substituição de Aminoácidos , Animais , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/metabolismo , Lipopolissacarídeos/toxicidade , Camundongos Transgênicos , Mutação de Sentido Incorreto , Fosforilação/efeitos dos fármacos , Fosforilação/genética , Serina/genética , Serina/metabolismo , Fator de Transcrição RelA/genética
12.
Nat Commun ; 7: 11869, 2016 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-27323669

RESUMO

Receptor-interacting protein kinase 3 (RIPK3) mediates necroptosis, a form of programmed cell death that promotes inflammation in various pathological conditions, suggesting that it might be a privileged pharmacological target. However, its function in glucose homeostasis and obesity has been unknown. Here we show that RIPK3 is over expressed in the white adipose tissue (WAT) of obese mice fed with a choline-deficient high-fat diet. Genetic inactivation of Ripk3 promotes increased Caspase-8-dependent adipocyte apoptosis and WAT inflammation, associated with impaired insulin signalling in WAT as the basis for glucose intolerance. Similarly to mice, in visceral WAT of obese humans, RIPK3 is overexpressed and correlates with the body mass index and metabolic serum markers. Together, these findings provide evidence that RIPK3 in WAT maintains tissue homeostasis and suppresses inflammation and adipocyte apoptosis, suggesting that systemic targeting of necroptosis might be associated with the risk of promoting insulin resistance in obese patients.


Assuntos
Tecido Adiposo Branco/enzimologia , Deficiência de Colina/genética , Intolerância à Glucose/genética , Gordura Intra-Abdominal/enzimologia , Necrose/enzimologia , Obesidade/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Adipócitos/enzimologia , Adipócitos/patologia , Tecido Adiposo Branco/patologia , Animais , Apoptose/genética , Índice de Massa Corporal , Caspase 8/genética , Caspase 8/metabolismo , Colina/metabolismo , Deficiência de Colina/enzimologia , Deficiência de Colina/etiologia , Deficiência de Colina/patologia , Dieta Hiperlipídica , Regulação da Expressão Gênica , Intolerância à Glucose/enzimologia , Intolerância à Glucose/etiologia , Intolerância à Glucose/patologia , Homeostase , Humanos , Inflamação , Insulina/metabolismo , Resistência à Insulina , Gordura Intra-Abdominal/patologia , Masculino , Camundongos , Necrose/genética , Necrose/patologia , Obesidade/enzimologia , Obesidade/etiologia , Obesidade/patologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo
13.
EMBO Mol Med ; 6(8): 1062-74, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24963148

RESUMO

Non-alcoholic fatty liver disease (NAFLD) represents the most common liver disease in Western countries and often progresses to non-alcoholic steatohepatitis (NASH) leading ultimately to liver fibrosis and liver cancer. The occurrence of hepatocyte cell death-so far characterized as hepatocyte apoptosis-represents a fundamental step from benign steatosis toward progressive steatohepatitis. In contrast, the function of RIP3-dependent "necroptosis" in NASH and NASH-induced fibrosis is currently unknown. We show that RIP3 is upregulated in human NASH and in a dietary mouse model of steatohepatitis. RIP3 mediates liver injury, inflammation, induction of hepatic progenitor cells/activated cholangiocytes, and liver fibrosis through a pathway suppressed by Caspase-8. This function of RIP3 is mediated by a positive feedback loop involving activation of Jun-(N)-terminal Kinase (JNK). Furthermore, RIP3-dependent JNK activation promotes the release of pro-inflammatory mediators like MCP-1, thereby attracting macrophages to the injured liver and further augmenting RIP3-dependent signaling, cell death, and liver fibrosis. Thus, RIP3-dependent necroptosis controls NASH-induced liver fibrosis. This pathway might represent a novel and specific target for pharmacological strategies in patients with NASH.


Assuntos
Regulação da Expressão Gênica , MAP Quinase Quinase 4/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Animais , Quimiocina CCL2 , Modelos Animais de Doenças , Humanos , Fígado/patologia , Camundongos
14.
J Crit Care ; 28(5): 882.e1-11, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23337484

RESUMO

INTRODUCTION: Inflammatory and autoimmune diseases have been associated with the tumor necrosis factor superfamily member "A PRoliferation Inducing Ligand" (APRIL). However, up to now, APRIL has not been investigated in critical illness or sepsis. We therefore analyzed APRIL serum concentrations in a large cohort of well-characterized intensive care unit patients. METHODS: Serum concentrations of APRIL were measured in 246 critically ill patients, of which 157 fulfilled sepsis criteria in comparison with 81 healthy controls. Clinical data were recorded and correlated with APRIL serum levels. RESULTS: We detected strongly elevated serum levels of APRIL in critically ill patients compared with healthy controls. Levels of APRIL were further elevated in sepsis and significantly correlated with classical markers of inflammation, bacterial infection, or multiorgan failure. Consequently, high APRIL levels were associated with an unfavorable prognosis and predicted mortality with higher diagnostic accuracy than established prognostic scoring systems such as the Acute Physiology and Chronic Health Evaluation II score. CONCLUSION: Serum levels of APRIL were significantly elevated in intensive care unit patients, with the highest concentrations in septic patients, and associated with unfavorable outcome. Besides being used as a single marker, APRIL may be implemented into established scoring systems to further improve their sensitivity and specificity in predicting patient's prognosis.


Assuntos
Sepse/sangue , Sepse/mortalidade , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Casos e Controles , Estado Terminal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes
15.
Cell Rep ; 4(4): 776-90, 2013 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-23972991

RESUMO

For years, the term "apoptosis" was used synonymously with programmed cell death. However, it was recently discovered that receptor interacting protein 3 (RIP3)-dependent "necroptosis" represents an alternative programmed cell death pathway activated in many inflamed tissues. Here, we show in a genetic model of chronic hepatic inflammation that activation of RIP3 limits immune responses and compensatory proliferation of liver parenchymal cells (LPC) by inhibiting Caspase-8-dependent activation of Jun-(N)-terminal kinase in LPC and nonparenchymal liver cells. In this way, RIP3 inhibits intrahepatic tumor growth and impedes the Caspase-8-dependent establishment of specific chromosomal aberrations that mediate resistance to tumor-necrosis-factor-induced apoptosis and underlie hepatocarcinogenesis. Moreover, RIP3 promotes the development of jaundice and cholestasis, because its activation suppresses compensatory proliferation of cholangiocytes and hepatic stem cells. These findings demonstrate a function of RIP3 in regulating carcinogenesis and cholestasis. Controlling RIP3 or Caspase-8 might represent a chemopreventive or therapeutic strategy against hepatocellular carcinoma and biliary disease.


Assuntos
Carcinogênese/metabolismo , Caspase 8/metabolismo , Proliferação de Células , Colestase/metabolismo , Fígado/metabolismo , MAP Quinase Quinase 4/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Animais , Apoptose , Carcinogênese/patologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Caspase 8/genética , Colestase/patologia , Hepatócitos/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Icterícia/metabolismo , Icterícia/patologia , Fígado/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , MAP Quinase Quinase 4/genética , Camundongos , Camundongos Knockout , Necrose , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Células-Tronco/metabolismo
16.
Cancer Cell ; 17(5): 481-96, 2010 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-20478530

RESUMO

The MAP3-kinase TGF-beta-activated kinase 1 (TAK1) critically modulates innate and adaptive immune responses and connects cytokine stimulation with activation of inflammatory signaling pathways. Here, we report that conditional ablation of TAK1 in liver parenchymal cells (hepatocytes and cholangiocytes) causes hepatocyte dysplasia and early-onset hepatocarcinogenesis, coinciding with biliary ductopenia and cholestasis. TAK1-mediated cancer suppression is exerted through activating NF-kappaB in response to tumor necrosis factor (TNF) and through preventing Caspase-3-dependent hepatocyte and cholangiocyte apoptosis. Moreover, TAK1 suppresses a procarcinogenic and pronecrotic pathway, which depends on NF-kappaB-independent functions of the I kappaB-kinase (IKK)-subunit NF-kappaB essential modulator (NEMO). Therefore, TAK1 serves as a gatekeeper for a protumorigenic, NF-kappaB-independent function of NEMO in parenchymal liver cells.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Hepáticas Experimentais/metabolismo , MAP Quinase Quinase Quinases/fisiologia , NF-kappa B/metabolismo , Animais , Apoptose , Transformação Celular Neoplásica , Hiperplasia , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Camundongos Transgênicos , Necrose
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