Sympathetic nervous system promotes hepatocarcinogenesis by modulating inflammation through activation of alpha1-adrenergic receptors of Kupffer cells.
Brain Behav Immun
; 59: 118-134, 2017 Jan.
Article
em En
| MEDLINE
| ID: mdl-27585737
ABSTRACT
The sympathetic nervous system (SNS) is known to play a significant role in tumor initiation and metastasis. Hepatocellular carcinoma (HCC) frequently occurs in cirrhotic livers after chronic inflammation, and the SNS is hyperactive in advanced liver cirrhosis. However, it remains unclear whether the SNS promotes hepatocarcinogenesis by modulating chronic liver inflammation. In this study, a retrospective pathological analysis and quantification of sympathetic nerve fiber densities (tyrosine hydroxylase, TH+) in HCC patients, and diethylnitrosamine (DEN)-induced hepatocarcinogenesis in rats were performed. Our data showed that high density of sympathetic nerve fibers and α1-adrenergic receptors (ARs) of Kupffer cells (KCs) were associated with a poor prognosis of HCC. Sympathetic denervation or blocking of α1-ARs decreased DEN-induced HCC incidence and tumor development. In addition, synergistic effects of interleukin-6 (IL-6) and transforming growth factor-beta (TGF-ß) in hepatocarcinogenesis were observed. The suppression of the SNS reduced IL-6 and TGF-ß expression, which suppressed hepatocarcinogenesis, and KCs play a key role in this process. After the ablation of KCs, IL-6 and TGF-ß expression and the development of HCC were inhibited. This study demonstrates that sympathetic innervation is crucial for hepatocarcinogenesis and that the SNS promotes hepatocarcinogenesis by activating α1-ARs of KCs to boost the activation of KCs and to maintain the inflammatory microenvironment. These results indicate that sympathetic denervation or α1-ARs blockage may represent novel treatment approaches for HCC.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sistema Nervoso Simpático
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Receptores Adrenérgicos alfa 1
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Carcinoma Hepatocelular
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Carcinogênese
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Inflamação
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Células de Kupffer
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Neoplasias Hepáticas
Tipo de estudo:
Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Adult
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Aged
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Animals
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Brain Behav Immun
Assunto da revista:
ALERGIA E IMUNOLOGIA
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CEREBRO
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PSICOFISIOLOGIA
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
China