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

AimsHere, we tested the hypothesis that glial responses via the production of cytokines such as transforming growth factor-beta 1 (TGF1) and tumour necrosis factor alpha (TNF), 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. MethodsHyh mice, which exhibit either severe or compensated long-lasting forms of hydrocephalus, were examined and compared with wild-type mice. TGF1, TNF and TNFR1 mRNA levels were quantified using real-time PCR. TNF and TNFR1 were immunolocalized in the brain tissues of hyh mice and four hydrocephalic human foetuses relative to astroglial and microglial reactions. ResultsThe TGF1 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 TNF and TNFR1, respectively, compared with normal mice. In the hyh mouse, TNF and TNFR1 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. TNF immunoreactivity was also detected in the glial reaction in the small group of human foetuses exhibiting hydrocephalus that were examined. ConclusionsIn the hyh mouse model of congenital hydrocephalus, TNF and TNFR1 appear to be associated with the severity of the disease, probably mediating the astrocyte reaction, neurodegenerative processes and ischaemia.