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首页> 外文期刊>The FEBS journal >Fragile X-related protein FXR1 controls post-transcriptional suppression of lipopolysaccharide-induced tumour necrosis factor-l production by transforming growth factor-o1
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Fragile X-related protein FXR1 controls post-transcriptional suppression of lipopolysaccharide-induced tumour necrosis factor-l production by transforming growth factor-o1

机译：脆弱的X相关蛋白FXR1通过转化生长因子o1控制转录后抑制脂多糖诱导的肿瘤坏死因子-1的产生

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摘要

Tumour necrosis factor-l (TNF-l) is a key mediator of inflammation in host defence against infection and in autoimmune disease. Its production is controlled post-transcriptionally by multiple RNA-binding proteins that interact with the TNF-l AU-rich element and regulate its expression; one of these is Fragile X mental retardation-related protein 1 (FXR1). The anti-inflammatory cytokine transforming growth factor-o1 (TGF-o1), which is involved in the homeostatic regulation of TNF-l, causes post-transcriptional suppression of lipopolysaccharide (LPS)-induced TNF-l production. We report here that this depends on FXR1. Using RAW 264.7 cells and bone marrow-derived macrophages (BMDMs) stimulated with LPS and TGF-o1, we show that TGF-o1 inhibits TNF-l protein secretion, whereas TNF-l mRNA expression remains unchanged. This response is recapitulated by the 3o-UTR of TNF-l, which is known to bind FXR1. TGF-o1 induces FXR1 with a pattern of expression distinct from that of tristetraprolin, T-cell intracellular antigen 1, or human antigen R. When FXR1 is knocked down, TGF-o1 is no longer able to inhibit LPS-induced TNF-l protein production, and overexpression of FXR1 suppresses LPS-induced TNF-l protein production. Targeting the p38 mitogen-activated protein kinase pathway of LPS-treated cells with small molecule inhibitors can induce FXR1 protein and mRNA expression. In summary, TGF-o1 opposes LPS-induced stabilization of TNF-l mRNA and reduces the amount of TNF-l protein, through induction of expression of the mRNA-binding protein FXR1.
机译：肿瘤坏死因子-1（TNF-1）是宿主抗感染和自身免疫疾病中炎症的关键介质。转录后由多种RNA结合蛋白控制其生成，这些蛋白与富含TNF-1 AU的元件相互作用并调节其表达;其中之一是脆性X智力低下相关蛋白1（FXR1）。抗肿瘤细胞因子转化生长因子-o1（TGF-o1）参与TNF-1的稳态调节，导致脂多糖（LPS）诱导的TNF-1产生转录后抑制。我们在这里报告，这取决于FXR1。使用LPS和TGF-o1刺激的RAW 264.7细胞和骨髓巨噬细胞（BMDMs），我们显示TGF-o1抑制TNF-1蛋白分泌，而TNF-1 mRNA表达保持不变。该应答被已知与FXR1结合的TNF-1的3o-UTR概括。 TGF-o1诱导FXR1的表达方式不同于Tristetraprolin，T细胞细胞内抗原1或人类抗原R。当FXR1被敲低时，TGF-o1不再能够抑制LPS诱导的TNF-1蛋白。 FXR1的过度表达会抑制LPS诱导的TNF-1蛋白的产生。用小分子抑制剂靶向LPS处理的细胞的p38丝裂原激活的蛋白激酶途径可以诱导FXR1蛋白和mRNA表达。总之，TGF-β1通过诱导mRNA结合蛋白FXR1的表达而反对LPS诱导的TNF-1 mRNA的稳定化并减少TNF-1蛋白的量。

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