Abstract
Periventricular leukomalacia (PVL) is the major cause of cerebral palsy (CP). The mechanisms of this lesion formation is not yet understood but cytokines have been implicated in it. We have developed a mouse model of PVL based on intraneocortical injection of ibotenate, a glutamate analog in a way to study the role of IL-9 (Interleukin 9). Studies had shown that newborns with higher levels of IL-9 were at higher risk to develop CP. In agreement with these data, research using our model has shown that pre-treatment with IL-9 exacerbated brain lesions induced by ibotenate. We have also shown that brain mast cells mediate the toxic effects of IL-9. The goal of this study is to identify the underlying pathophysiological mechanism. Our results showed that neuronal TGF-beta-1 (Tranforming Growth Factor beta 1) plays a key role in the toxic effects of IL-9: -pre-treatment with TGF-beta-1 produced the same effects as IL-9 on lesions. IL-9 effects were abolished when a specific TGF-beta-1 neutralizing antibody is administered at the same time. -real time PCR, Western blot, and immunohistochemistry showed that pre-treatment with IL-9 increased TGF-beta-1 neocortical expression. In vitro studies demonstrated that neurons were the major contributor in IL-9-induced increase of TGF-beta-1. -in c-Kit mast cell-deficient mice, TGF-beta-1 failed to exacerbate lesions. A specific inhibitor of mast cell degranulation and histamine receptor blockers abrogated TGF-beta-1 effects, suggesting a key role of mast cells and histamine in TGF-beta-1 effects. In vitro studies using a mast cell line showed that TGF-beta-1 increased histamine in the supernatant. In conclusion, these data support the notion that neuronal TGF-beta-1 plays a key role in the IL-9/mast cell interaction, which leads to an exacerbation of neonatal damage through an increased extracellular histamine concentration. The identification of this new pathway might have important implications for understanding CP.
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Fontaine, R., Mesples, B., Lelievre, V. et al. 125 TGF-Beta-1 Mediates IL-9/Mast Cells Interactions in a Mouse Model of Periventricular Leukomalacia. Pediatr Res 58, 376 (2005). https://doi.org/10.1203/00006450-200508000-00154
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DOI: https://doi.org/10.1203/00006450-200508000-00154