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.
OBJECTIVE
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.
Department of Cell Biology, Genetics, and Physiology, Faculty of Sciences, University of Malaga, Malaga, Spain.
Antonio-Jesús
AJ
Jiménez
Luis-Manuel
LM
Rodríguez-Pérez
María-Dolores
MD
Domínguez-Pinos
María-Carmen
MC
Gómez-Roldán
María
M
García-Bonilla
Ailec
A
Ho-Plagaro
Ruth
R
Roales-Buján
Sebastián
S
Jiménez
María-Carmen
MC
Roquero-Mañueco
María-Isabel
MI
Martínez-León
María-Luisa
ML
García-Martín
Manuel
M
Cifuentes
Bienvenido
B
Ros
Miguel-Ángel
MÁ
Arráez
Javier
J
Vitorica
Antonia
A
Gutiérrez
José-Manuel
JM
Pérez-Fígares
D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005333:Fetus; D006801:Humans; D006849:Hydrocephalus / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D017628:Microglia / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012720:Severity of Illness Index; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha
TGFβ1; TNFα; biomarkers; congenital hydrocephalus; microglia; reactive astrocyte