Metabolic Inflammation-Associated IL-17A Causes Non-alcoholic Steatohepatitis and Hepatocellular Carcinoma

Gomes, Ana L.; Teijeiro, Ana; Burén, Stefan; Tummala, Krishna Seshu; Yilmaz, M. Deniz; Waisman, Ari; Theurillat, Jean-Philippe; Perna, Cristian; Djouder, Nabil

doi:10.1016/j.ccell.2016.05.020

Cited by 307 publications

(330 citation statements)

References 43 publications

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“…The inflammatory response seems to be an important mediator of many NAFLD-associated outcomes such as the HCC by creating an inflammatory microenvironment (28, 51), cardiovascular disease by promoting atherogenesis (52, 53). Table 1 summarizes the clinical studies that have assessed the role of general inflammatory biomarkers and cytokines to predict outcomes in NAFLD.…”

Section: An Overview Of the Predictive Role Of General Inflammatory Bmentioning

confidence: 99%

“…Th17 cells secrete the IL-17, IL-21, and e IL-22, being important in immunity against extracellular infectious agents such as bacteria and fungi but also contribute in the immunopathogenesis of many diseases such as psoriasis and tumors (51, 91–93). IL-17 is the most studied Th17-secreted cytokine in liver disease (15, 41, 42).…”

Section: Underlying Mechanisms Pathways and Relationship Between Cementioning

confidence: 99%

“…The maintenance of these imbalances seems to favor the inflammatory microenvironment, which would explain their prognostic implications, and therapeutics potentials, from NAFLD, to cirrhosis, and HCC (28, 51). In addition, the role of the IL-17 axis in fibrogenesis has been shown in organs other than the liver, including the heart (119, 120), lung (121), and kidney (122).…”

Section: Underlying Mechanisms Pathways and Relationship Between Cementioning

confidence: 99%

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Immune Imbalances in Non-Alcoholic Fatty Liver Disease: From General Biomarkers and Neutrophils to Interleukin-17 Axis Activation and New Therapeutic Targets

Paquissi

2016

Front. Immunol.

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Non-alcoholic fatty liver disease (NAFLD) is an increasing problem worldwide and is associated with negative outcomes such as cirrhosis, hepatocellular carcinoma, insulin resistance, diabetes, and cardiovascular events. Current evidence shows that the immune response has an important participation driving the initiation, maintenance, and progression of the disease. So, various immune imbalances, from cellular to cytokines levels, have been studied, either for better compression of the disease pathophysiology or as biomarkers for severity assessment and outcome prediction. In this article, we performed a thorough review of studies that evaluated the role of inflammatory/immune imbalances in the NAFLD. At the cellular level, we gave special focus on the imbalance between neutrophils and lymphocytes counts (the neutrophil-to-lymphocyte ratio), and that which occurs between T helper 17 (Th17) and regulatory T cells as emerging biomarkers. By extension, we reviewed the reflection of these imbalances at the molecular level through pro-inflammatory cytokines including those involved in Th17 differentiation (IL-6, IL-21, IL-23, and transforming growth factor-beta), and those released by Th17 cells (IL-17A, IL-17F, IL-21, and IL-22). We gave particular attention to the role of IL-17, either produced by Th17 cells or neutrophils, in fibrogenesis and steatohepatitis. Finally, we reviewed the potential of these pathways as new therapeutic targets in NAFLD.

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Section: An Overview Of the Predictive Role Of General Inflammatory Bmentioning

confidence: 99%

Section: Underlying Mechanisms Pathways and Relationship Between Cementioning

confidence: 99%

Section: Underlying Mechanisms Pathways and Relationship Between Cementioning

confidence: 99%

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Immune Imbalances in Non-Alcoholic Fatty Liver Disease: From General Biomarkers and Neutrophils to Interleukin-17 Axis Activation and New Therapeutic Targets

Paquissi

2016

Front. Immunol.

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“…The crucial role of innate immunity in NASH-HCC development was supported by a recent study that demonstrated that the suppression of Th17 cell differentiation or blocking IL17A signaling prevents NASH and subsequent HCC development (9). Moreover, an elegant study emphasized the importance of gut microbiota in NASH progression and noted that senescent hepatic stellate cells (HSC) may be critical for the transformation of steatotic hepatocytes to malignant cells (10).…”

Section: Introductionmentioning

confidence: 99%

JCAD Promotes Progression of Nonalcoholic Steatohepatitis to Liver Cancer by Inhibiting LATS2 Kinase Activity

et al. 2017

Cancer Research

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Nonalcoholic steatohepatitis-associated hepatocellular carcinoma (NASH-HCC) is a malignancy whose incidents are rapidly increasing. However, the mechanisms that drive development of HCC in a steatotic microenvironment remain unknown. Here we report that the obesity-associated protein JCAD is expressed at significantly higher levels in human NASH-HCC specimens compared with pericarcinoma specimens. High JCAD expression was verified in multiple hepatoma cell lines. Forced overexpression of JCAD in hepatoma cells promoted tumor growth and proliferation, whereas JCAD silencing yielded opposite effects. JCAD interacted with the kinase domain of the tumor suppressor kinase LATS2, a core component of the Hippo signaling pathway. JCAD overexpression inhibited the ability of LATS2 to phosphorylate YAP in this pathway, in turn upregulating CCND1 and GLI2 to promote hepatoma cell proliferation. JCAD was induced by fatty acid overload in hepatic cells and was highly expressed in a mouse model of NASH-precarcinoma lesions, where the ratio of phospho-YAP to YAP was decreased. In human NASH-HCC specimens, JCAD expression and YAP phosphorylation patterns paralleled with the mouse model. Our findings illuminate a new role for JCAD and its critical interplay in the Hippo signaling cascade during the transition of NASH to HCC, with potential implications for therapeutic development in this setting.

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“…Because immune cells may induce different reactions between the skin and the liver, it is necessary to test the probiotics in an orthotopic model, as the authors are planning. Gomes et al recently reported that IL-17 promotes HCC by inducing insulin resistance in the adipose tissue (13), suggesting that additional mechanisms are involved in tumor suppression. However, the role of Th17 is not so simple.…”

Section: Editorial On Nutritionmentioning

confidence: 99%

The day will come to treat HCC in a drugstore?

Miura¹

2017

Hepatobiliary Surg. Nutr.

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Metabolic Inflammation-Associated IL-17A Causes Non-alcoholic Steatohepatitis and Hepatocellular Carcinoma

Cited by 307 publications

References 43 publications

Immune Imbalances in Non-Alcoholic Fatty Liver Disease: From General Biomarkers and Neutrophils to Interleukin-17 Axis Activation and New Therapeutic Targets

Immune Imbalances in Non-Alcoholic Fatty Liver Disease: From General Biomarkers and Neutrophils to Interleukin-17 Axis Activation and New Therapeutic Targets

JCAD Promotes Progression of Nonalcoholic Steatohepatitis to Liver Cancer by Inhibiting LATS2 Kinase Activity

The day will come to treat HCC in a drugstore?

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