Abstract
In a clinical trial of cerebral palsy, the level of plasma interleukin-8 (IL-8) was increased, correlated with motor improvement, after human umbilical cord blood mononuclear cell (hUCBC) infusion. This study aimed to elucidate the role of IL-8 in the therapeutic effects of hUCBCs in a mouse model of hypoxic-ischaemic brain injury (HI). In P7 HI mouse brains, hUCBC administration at day 7 after HI upregulated the gene expression of Cxcl2, the mouse IL-8 homologue and increased the expression of its receptor, CXCR2. hUCBC administration restored the sequential downstream signalling axis of p-p38/p-MAPKAPK2, NFκB, and angiogenic factors, which were downregulated by HI. An in vitro assay revealed the downregulation of the angiogenic pathway by CXCR2 knockdown and p38 inhibition. In vivo p38 inhibition prior to hUCBC administration in HI mouse brains produced identical results. Behavioural outcomes revealed a therapeutic effect (ps < 0.01) of hUCBC or IL-8 administration, which was correlated with decreases in infarct size and angiogenic findings in the striatum. In conclusion, the response of the host to hUCBC administration in mice upregulated Cxcl2, which led to the activation of the IL-8-mediated p-p38 signalling pathway. The upregulation of the downstream pathway and angiogenic growth factors via NFκB can be inferred to be the potential therapeutic mechanism of hUCBCs.
Highlights
Cerebral palsy is the most common cause of severe motor disability that exists throughout life from the early childhood period and is attributed to injury in the developing brain[1,2]
We demonstrated that human umbilical cord blood mononuclear cell (hUCBC) induced the activation of an IL-8-mediated angiogenic cascade in a mouse hypoxic-ischaemic brain injury (HI) model
Following hUCBC administration, the upregulation of the IL-8 homologue Cxcl[2] and its receptor CXCR2, the phosphorylation of the downstream molecules p38 and MAPKAPK2, the degradation of IκB, leading to NFκB activation, and the upregulation of angiogenic growth factors and the endothelial marker CD31 all occurred in a consecutive manner beginning on the day
Summary
Cerebral palsy is the most common cause of severe motor disability that exists throughout life from the early childhood period and is attributed to injury in the developing brain[1,2]. The following potential signalling molecules in the IL-8-related angiogenic pathway were included in the experiment: Cxcl[2], a representative mouse homologue of IL-8; CXCR2, the transmembrane receptor for IL-8; p38 mitogen-activated protein kinase (MAPK); and the transcription factor nuclear factor kappa B (NFκB). IL-8-mediated p38 MAPK signalling and angiogenic gene expression following hUCBC administration were examined in HI mouse brain tissue in vivo and in mouse microvascular endothelial cells in vitro. The upregulation of the angiogenic genes and the endothelial marker CD31 in conjunction with NFκB activation was investigated to establish the therapeutic mechanism of hUCBCs. In addition, the therapeutic effect of hUCBCs was evaluated through behavioural assessments and brain infarct size measurements in comparison with other treatments after HI. Cyclosporine was used as an adjuvant for the suppression of the host immune response in hUCBC-treated mice
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