儿童噬血性淋巴组织细胞增生症GDF15表达研究及高铁蛋白血症机制初探

Expression of GDF15 and implication in the development hyperferritinemia in children with HLH: a pilot study

目的研究噬血性淋巴组织细胞增生症(HLH)患儿外周血细胞生长分化因子15(GDF15)和细胞铁稳态调节相关分子mRNA表达情况,探讨HLH高铁蛋白血症发生机制。方法 HLH组为18例初诊HLH患儿,对照组为19例健康儿童。EvaGreen荧光定量RT-PCR检测相关基因mRNA表达水平,2-Ct方法计算基因相对表达量。结果 HLH组GDF15mRNA的中位表达量高于对照组,差异有统计学意义(4.584对1.490,P<0.05);HLH组铁转出蛋白(Fpn)、铁蛋白重链(Fn-H)和铁调节蛋白2(IRP2)mRNA的相对表达量高于对照组,差异均有统计学意义(P均<0.05),而细胞内铁感知蛋白FBXL5 mRNA中位表达量低于对照组,差异有统计学意义(P<0.05)。实验组GDF15表达量与Fpn和Fn-H表达量呈正相关。结论 HLH患儿GDF15表达显著上调,有助于抑制巨噬细胞进一步活化。HLH患儿Fpn和Fn-H表达显著上调,并与GDF15呈正相关,提示巨噬细胞异常持续活化和细胞因子风暴,显著促进Fn-H的转录和分泌,而GDF介导的Fpn表达上调,促进细胞内铁转出,很可能为HLH高铁蛋白血症发生的2个关键机制。

Objective To study the mRNA expressions of growth differentiation factor 15 （GDF15） and key molecules of cellular iron metabolism in peripheral blood cells of children with hemophagocytic lymphohistiocytosis （HLH）, and to explore the implications of GDF15 in the development of hyperferritinemia in HLH. Methods Eighteen children with newly-diagnosed HLH and 19 healthy children were enrolled. The mRNA expression of target genes was determined by EvaGreen real-time RT-PCR. The relative mRNA expression level was represented by target gene expression against house- keeping beta-actin using the comparative CT. method. Results The median mRNA expression of GDF15 in HLH group was significantly higher than that in control group （4.584 vs 1.490, P=0.039）. Similarly, the mRNA expression levels of ferroportin （Fpn）, ferritin heavy chain （Fn-H） and iron regulatory protein 2 （IRP2） were significantly up-regulated in HLH group （all P〈0.05）. However, the median mRNA expression of F-box and Leucine-rich Repeat Protein 5 （FBXL5） were sig- nificantly lower than that in control group （P=0.025）. In addition, the GDF15 expression was positively correlated with the expressions of Fpn and Fn-H in HLH group. Conclusions Up-regulation of GDF15 in HLH helps to suppress further activa- tion of macrophages. Importantly, it is found that GDF15-associated induction of ferroportin, together with enhanced fer- ritin transcription triggered by abnormal activation of macrophages and hypercytokinemia in HLH, which highly suggests that increased ferritin secretion and ferroportin-mediated cellular iron efflux might be the two key mechanisms responsible for the development of hyperferritinemia in HLH.