在骨髓衍生的肥大细胞分化过程中，KLF4是抑制多胺抑制组胺合成所必需的。,PLOS ONE

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在骨髓衍生的肥大细胞分化过程中，KLF4是抑制多胺抑制组胺合成所必需的。
PLOS ONE ( IF 2.9 ) Pub Date : 2020-02-26 , DOI: 10.1371/journal.pone.0229744
Kazuhiro Nishimura ₁ , Moemi Okamoto ₁ , Rina Shibue ₁ , Toshio Mizuta ₁ , Toru Shibayama ₁ , Tetsuhiko Yoshino ₁ , Teruki Murakami ₁ , Masashi Yamaguchi ₂ , Satoshi Tanaka ₃ , Toshihiko Toida ₁ , Kazuei Igarashi _{1,

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Affiliation

肥大细胞具有包含化学介质例如组胺的分泌颗粒，并且在免疫系统中起重要作用。多胺是细胞过程如基因表达和翻译的必要因素。据报道，分泌颗粒含有组胺和多胺，它们具有相似的化学结构，是由阳离子氨基酸的代谢产生的。我们使用骨髓衍生的肥大细胞（BMMC）研究了多胺耗竭对肥大细胞的影响。使用α-二氟甲基鸟氨酸（DFMO）（鸟氨酸脱羧酶的不可逆抑制剂）诱导多胺消耗。DFMO处理导致BMMC中细胞数量的显着减少和异常分泌颗粒的减少。此外，细胞显示为2。在BMMC分化过程中，转录水平的细胞内组胺增加3倍，组氨酸脱羧酶（HDC）上调。DFMO处理后，转录因子kruppel样因子4（KLF4）的水平大大降低。但是，Klf4 mRNA的表达水平与对照相似。我们使用编码Klf4-luc2融合mRNA的报告基因确定了用于转染NIH3T3细胞的KLF4的翻译调控，并进行了体外翻译。我们发现，不管起始密码子的识别如何，Klf4 mRNA上存在富含GC的5'-非翻译区（5'-UTR），可以提高DFMO处理对KLF4合成的效率。综上所述，这些结果表明DFMO对组胺合成的增强取决于Hdc表达的上调，

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KLF4 is required for suppression of histamine synthesis by polyamines during bone marrow-derived mast cell differentiation.

Mast cells have secretory granules containing chemical mediators such as histamine and play important roles in the immune system. Polyamines are essential factors for cellular processes such as gene expression and translation. It has been reported that secretory granules contain both histamine and polyamines, which have similar chemical structures and are produced from the metabolism of cationic amino acids. We investigated the effect of polyamine depletion on mast cells using bone marrow-derived mast cells (BMMCs). Polyamine depletion was induced using α-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase. DFMO treatment resulted in a significant reduction of cell number and abnormal secretory granules in BMMCs. Moreover, the cells showed a 2.3-fold increase in intracellular histamine and up-regulation of histidine decarboxylase (HDC) at the transcriptional level during BMMC differentiation. Levels of the transcription factor kruppel-like factor 4 (KLF4) greatly decreased upon DFMO treatment; however, Klf4 mRNA was expressed at levels similar to controls. We determined the translational regulation of KLF4 using reporter genes encoding Klf4-luc2 fusion mRNA, for transfecting NIH3T3 cells, and performed in vitro translation. We found that the efficiency of KLF4 synthesis in response to DFMO treatment was enhanced by the existence of a GC-rich 5'-untranslated region (5'-UTR) on Klf4 mRNA, regardless of the recognition of the initiation codon. Taken together, these results indicate that the enhancement of histamine synthesis by DFMO depends on the up-regulation of Hdc expression, achieved by removal of transcriptional suppression of KLF4, during differentiation.

更新日期：2020-02-27

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