Increased levels of tumour necrosis factor alpha (TNFα) but not transforming growth factor-beta 1 (TGFβ1) are associated with the severity of congenital hydrocephalus in the hyh mouse

Authors

  • Antonio-Jesús Jiménez,

    Corresponding author
    1. Department of Cell Biology, Genetics, and Physiology, Faculty of Sciences, University of Malaga, Malaga, Spain
    • Correspondence: Antonio-J Jiménez, Departamento de Biología Celular, Genética y Fisiología, Facultad de Ciencias, Campus de Teatinos, Universidad de Málaga, E-29071-Málaga, Spain. Tel: +34 952 133 343; Fax: +34 952 132 000; E-mail: ajjimenez@uma.es

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  • Luis-Manuel Rodríguez-Pérez,

    1. Department of Cell Biology, Genetics, and Physiology, Faculty of Sciences, University of Malaga, Malaga, Spain
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  • María-Dolores Domínguez-Pinos,

    1. Department of Cell Biology, Genetics, and Physiology, Faculty of Sciences, University of Malaga, Malaga, Spain
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  • María-Carmen Gómez-Roldán,

    1. Department of Cell Biology, Genetics, and Physiology, Faculty of Sciences, University of Malaga, Malaga, Spain
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  • María García-Bonilla,

    1. Department of Cell Biology, Genetics, and Physiology, Faculty of Sciences, University of Malaga, Malaga, Spain
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  • Ailec Ho-Plagaro,

    1. Department of Cell Biology, Genetics, and Physiology, Faculty of Sciences, University of Malaga, Malaga, Spain
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  • Ruth Roales-Buján,

    1. Department of Cell Biology, Genetics, and Physiology, Faculty of Sciences, University of Malaga, Malaga, Spain
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  • Sebastián Jiménez,

    1. Department of Biochemistry and Cell Biology, Faculty of Pharmacy, University of Sevilla, Sevilla, Spain
    2. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
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  • María-Carmen Roquero-Mañueco,

    1. Department of Cell Biology, Genetics, and Physiology, Faculty of Sciences, University of Malaga, Malaga, Spain
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  • María-Isabel Martínez-León,

    1. Neurodiagnostic Section, Department of Paediatric Radiology, University Regional Hospital Carlos Haya, Malaga, Spain
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  • María-Luisa García-Martín,

    1. Nanoimaging Unit, Bionand, Malaga, Spain
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  • Manuel Cifuentes,

    1. Department of Cell Biology, Genetics, and Physiology, Faculty of Sciences, University of Malaga, Malaga, Spain
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  • Bienvenido Ros,

    1. Paediatric Neurosurgery Section, Department of Neurosurgery, University Regional Hospital Carlos Haya, Malaga, Spain
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  • Miguel-Ángel Arráez,

    1. Paediatric Neurosurgery Section, Department of Neurosurgery, University Regional Hospital Carlos Haya, Malaga, Spain
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  • Javier Vitorica,

    1. Department of Biochemistry and Cell Biology, Faculty of Pharmacy, University of Sevilla, Sevilla, Spain
    2. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
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  • Antonia Gutiérrez,

    1. Department of Cell Biology, Genetics, and Physiology, Faculty of Sciences, University of Malaga, Malaga, Spain
    2. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
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  • José-Manuel Pérez-Fígares

    1. Department of Cell Biology, Genetics, and Physiology, Faculty of Sciences, University of Malaga, Malaga, Spain
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Abstract

Aims

Here, we tested the hypothesis that glial responses via the production of cytokines such as transforming growth factor-beta 1 (TGFβ1) and tumour necrosis factor alpha (TNFα), which play important roles in neurodegenerative diseases, are correlated with the severity of congenital hydrocephalus in the hyh mouse model. We also searched for evidence of this association in human cases of primary hydrocephalus.

Methods

Hyh mice, which exhibit either severe or compensated long-lasting forms of hydrocephalus, were examined and compared with wild-type mice. TGFβ1, TNFα and TNFαR1 mRNA levels were quantified using real-time PCR. TNFα and TNFαR1 were immunolocalized in the brain tissues of hyh mice and four hydrocephalic human foetuses relative to astroglial and microglial reactions.

Results

The TGFβ1 mRNA levels were not significantly different between hyh mice exhibiting severe or compensated hydrocephalus and normal mice. In contrast, severely hydrocephalic mice exhibited four- and two-fold increases in the mean levels of TNFα and TNFαR1, respectively, compared with normal mice. In the hyh mouse, TNFα and TNFαR1 immunoreactivity was preferentially detected in astrocytes that form a particular periventricular reaction characteristic of hydrocephalus. However, these proteins were rarely detected in microglia, which did not appear to be activated. TNFα immunoreactivity was also detected in the glial reaction in the small group of human foetuses exhibiting hydrocephalus that were examined.

Conclusions

In the hyh mouse model of congenital hydrocephalus, TNFα and TNFαR1 appear to be associated with the severity of the disease, probably mediating the astrocyte reaction, neurodegenerative processes and ischaemia.

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