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Cytokines and Cytokine-Receptors in the Pathogenesis of Alcoholic Hepatitis

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Universitat de Barcelona. Facultat de Medicina

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[spa] El consumo de alcohol es una de las causas más importantes de mortalidad que pueden prevenirse en nuestro país. La hepatitis alcohólica (HA) se caracteriza por un proceso de inflamación hepática (fundamentalmente por infiltración de células polimorfonucleares), esteatosis masiva hepática, fibrosis pericelular y daño hepatocelular. En la actualidad no existen tratamientos efectivos para el tratamiento de la HA y por esta razón, existe una clara necesidad de identificar nuevas dianas terapéuticas para tratar a estos pacientes en los diferentes estadios de la enfermedad (esteatosis, inflamación y/o fibrogénesis). El objetivo principal de esta tesis fue investigar nuevas dianas terapéuticas para el tratamiento de la HA. Para alcanzar dicho objetivo, realizamos estudios traslacionales que permitieran identificar marcadores biológicos alterados en muestras humanas procedentes de hígados de pacientes con HA para estudiar la función que tienen en el desarrollo de la enfermedad in vitro e in vivo en modelos animales de diferentes tipos de daño hepático y valorar si podrían considerarse como dianas terapéuticas. Mediante la performación de nuestros estudios, identificamos a la vía de citoquinas-receptores de citoquinas como una de las vías con el mayor número de genes diferentemente regulados en pacientes con HA con respecto a controles sanos. Estudios en muestras humanas y en modelos animales de daño hepático nos permitieron identificar al receptor de citoquinas Fn14 y a la citoquina CCL20 como importantes mediadores de la HA, correlacionados tanto con aspectos clínicos característicos así como con la gravedad de la enfermedad. La vía de citoquinas y receptores de citoquinas y, de manera específica Fn14 y CCL20 han sido identificados como novedosos mediadores implicados en la patogénesis de la HA y por lo tanto como potenciales dianas terapéuticas. Por lo tanto, gracias a la identificación de un patrón de los genes diferentemente regulados en la HA, nuestros datos proporcionan importantes resultados novedosos para el estudio de la patogénesis de la HA.

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[eng] By performing a translational study we identified a specific pattern of genes differentially regulated in patients with severe alcoholic hepatitis (AH). A functional analysis of the gene expression profile showed several pathways deregulated in AH, including cytokines- cytokine receptor interaction. Within cytokine-cytokine receptor interaction pathway, Fn14 has been identified as the only receptor belonging to TNF superfamily to be exclusively up-regulated in patients with AH, and its expression has been shown to be associated with severity of the disease and mortality. We observed that Fn14 is upregulated in experimental models of progenitor cell expansion and co-expressed with Ep-CAM in livers of patients with AH, suggesting that Fn14 may regulate ductular reaction expansion. Moreover, we showed that Fn14 hepatic expression is regulated by ethanol and pro-fibrogenic factors, suggesting that alcohol abuse together with fibrogenic mediators may be directly responsible for the induction of Fn14 expression in ALD. Furthermore, transcriptome analysis identified CCL20 as the most up-regulated cytokine in the liver of patients with AH. Hepatic expression and serum levels of CCL20 have been found elevated in patients with AH and have been showed to be associated with key clinical features of the disease such as fibrosis, endotoxemia and short-term mortality. These data suggest that besides playing a role in AH pathogenesis, CCL20 may also be considered as a potential non-invasive biomarker. We found that CCL20 hepatic expression is up-regulated in acute, chronic and acute-on chronic experimental model of liver injury induced by carbon tetrachloride (CCl4) and lipopolysaccharide (LPS) and their combination, respectively. Macrophages and hepatic stellate cells have been identified as the main CCL20 producing cell types in experimental models of acute-on-chronic liver injury. Moreover, we have showed that CCL20 exerts pro-fibrogenic and pro-inflammatory and effects on primary human hepatic stellate cells and on macrophages, suggesting that CCL20 may participate in both hepatic fibrosis and inflammation during liver disease in an autocrine and paracrine manner. Finally, we have found that CCL20 mediates LPS-induced liver injury by promoting hepatocellular apoptosis, expression of pro-inflammatory and pro-fibrogenic mediators and by enhancing macrophages and neutrophils infiltrate recruitment. In conclusion, during this thesis we performed two studies leading to the identification of new potential targets for therapy in AH. The identification of Fn14 and CCL20 as new potential targets for therapy in AH and their correlations with key hallmarks of the disease such as ethanol consumption, fibrosis, progenitor cells expansion and endotoxemia underline the complexity of this disease and the crosstalk between many mediators that occurs in AH. The data presented in this thesis suggest that cytokines and cytokine-receptor pathway could represent a new potential target for therapy in ALD; and also provide new important insights and a useful resource for the study of the pathogenesis of this disease.

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Cytokines and Cytokine-Receptors in the Pathogenesis of Alcoholic Hepatitis