Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Elevated mean IL-9 serum levels have been observed in human neonates who will later develop cerebral palsy. In earlier studies, using a newborn mouse model of excitotoxic lesions mimicking those described in human cerebral palsy, we found that IL-9 pretreatment exacerbated brain damage produced by intracerebral injections of the glutamatergic analog ibotenate. Among its different cell targets, the Th2 cytokine IL-9 is a mast cell growth and differentiation factor that can cause mast cells to release various substances including histamine. In the present study, we sought to determine whether the deleterious effects of IL-9 in our mouse model were mediated by mast cells through histamine release. All mouse pups were pretreated with intraperitoneal injections of IL-9 or saline between postnatal days (P) P1 and P5. Immunohistochemistry for murine mast cell protease-1 performed on P5 showed an increased density of labeled cells in the neopallium of IL-9-treated Swiss pups as compared with controls. Western blot analysis confirmed the increased murine mast cell protease-1 brain content of IL-9-treated Swiss mice. IL-9 pretreatment had no significant effect on ibotenate-induced excitotoxic brain lesions in mast cell-deficient P5 pups (WBB6F1/J kit(W/W-v)), whereas IL-9 exacerbated these lesions in the control littermates with normal mast cell populations. Finally, cromoglycate or antihistamine drugs significantly reduced ibotenate-induced brain lesions in IL-9-treated Swiss pups. Taken together, these data suggest that recruitment of cerebral mast cells with histamine release may contribute to the exacerbation of neonatal excitotoxic brain lesions produced by IL-9. Neuroprotective strategies targeting mast cells may be useful in some neonates at risk for cerebral palsy.
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PMID:Deleterious effects of IL-9-activated mast cells and neuroprotection by antihistamine drugs in the developing mouse brain. 1147 7

Intraneocortical injection of ibotenate, a glutamate analog, in newborn mice produces damage mimicking lesions observed in human infants with cerebral palsy. Previous research using this model has demonstrated that pretreatment with IL-9, a Th2 cytokine, significantly exacerbated excitotoxic brain lesions. The goal of this study is to identify the underlying pathophysiological mechanism of lesion formation. Pretreatment with TGF-beta1 produced the same effects as IL-9 on ibotenate-induced lesions. IL-9 effects were abolished when a specific TGF-beta1 neutralizing antibody is administered at the same time. Real-time PCR, Western blot, and immunohistochemistry showed that pretreatment with IL-9 increased TGF-beta1 neocortical expression. In vitro studies using real-time PCR and immunocytochemistry demonstrated that neurons were a major contributor in IL-9-induced increase of TGF-beta1. In c-Kit mast cell-deficient mice, TGF-beta1 failed to exacerbate excitotoxic brain lesions, suggesting a key role of mast cells in TGF-beta1 effects. A specific inhibitor of mast cell degranulation and histamine receptor blockers abrogated TGF-beta1 effects on excitotoxic lesions, providing further evidence of mast cell involvement and the role of mast cell-derived histamine. Finally, in vitro studies using a mast cell line showed that TGF-beta1 increased histamine in the supernatant. In aggregate, these data support the notion that neuronal TGF-beta1 plays a key role in the IL-9/mast cell interaction, which leads to an exacerbation of neonatal excitotoxic damage through an increased extracellular histamine concentration. The identification of this pathway, if confirmed in human neonates, might have important implications for understanding and preventing cerebral palsy.
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PMID:Neuronal TGF-beta1 mediates IL-9/mast cell interaction and exacerbates excitotoxicity in newborn mice. 1564 10