Poirier René, Lemaire Irma, Lemaire Simon
Department of Cellular and Molecular Medicine, University of Ottawa, Canada.
FEBS J. 2006 Sep;273(18):4360-73. doi: 10.1111/j.1742-4658.2006.05444.x.
Two histone H4 mRNA variants, H4-v.1 and histogranin mRNAs, were detected in the rat genome and measured in various tissues and isolated alveolar macrophages. Medium to high levels of both mRNAs were present in the liver, adrenal glands, thymus, bone marrow and alveolar macrophages. H4-v.1 cDNA contained an open reading frame that coded for unmodified whole histone H4, whereas histogranin cDNA lacked the first ATG codon and contained an open reading frame that coded for modified (Thr89) H4-(84-102). The two genes displayed a sequence homologous (> 80%) to the open reading frame of core H4 somatic (H4s) and H4 germinal (H4g) and their variant nature was supported by the absence of histone consensus palindromic and purine-rich sequences in the proximal 3'UTR, and the presence of a polyadenylation signal in the distal 3'UTR and of specific upstream transcription factor-binding sites. H4-v.1 and histogranin transcripts, but not H4s transcript, were selectively induced by lipopolysaccharide and/or interferon gamma in alveolar macrophages. In vitro transcription/translation experiments with H4-v.1 and histogranin cDNA pCMV constructs produced peptides with the molecular mass (2 kDa) of the alternative histone H4 translation product which, like synthetic H4-(86-100) and [Thr89]H4-(86-100) or rat histogranin, inhibited lipopolysaccharide-induced prostaglandin E(2) release from rat alveolar macrophages. The synthetic peptides also inhibited the secretion of the CXC chemokine interleukin-8 (GRO/CINC-1) in response to lipopolysaccharide. The presence of H4-v.1 and histogranin mRNAs in tissues wherein immune reactions take place and the inhibitory effects of their translation products on prostaglandin E(2) and interkeukin-8 secretion by activated alveolar macrophages suggest an anti-inflammatory function.
在大鼠基因组中检测到两种组蛋白H4 mRNA变体，即H4-v.1和组织粒蛋白mRNA，并在各种组织和分离的肺泡巨噬细胞中进行了测量。肝脏、肾上腺、胸腺、骨髓和肺泡巨噬细胞中均存在中等至高水平的这两种mRNA。H4-v.1 cDNA包含一个编码未修饰的完整组蛋白H4的开放阅读框，而组织粒蛋白cDNA缺少第一个ATG密码子，并包含一个编码修饰的（Thr89）H4-（84-102）的开放阅读框。这两个基因与核心H4体细胞（H4s）和H4生殖细胞（H4g）的开放阅读框显示出序列同源性（>80%），并且它们的变体性质得到近端3'UTR中缺乏组蛋白共有回文和富含嘌呤序列、远端3'UTR中存在多聚腺苷酸化信号以及特定上游转录因子结合位点的支持。H4-v.1和组织粒蛋白转录本，而非H4s转录本，在肺泡巨噬细胞中被脂多糖和/或干扰素γ选择性诱导。用H4-v.1和组织粒蛋白cDNA pCMV构建体进行的体外转录/翻译实验产生了分子量为2 kDa的替代组蛋白H4翻译产物的肽，该肽与合成的H4-（86-100）和[Thr89]H4-（86-100）或大鼠组织粒蛋白一样，抑制脂多糖诱导的大鼠肺泡巨噬细胞中前列腺素E2的释放。合成肽还抑制了脂多糖刺激下CXC趋化因子白细胞介素-8（GRO/CINC-1）的分泌。在发生免疫反应的组织中存在H4-v.1和组织粒蛋白mRNA，以及它们的翻译产物对活化肺泡巨噬细胞分泌前列腺素E2和白细胞介素-8的抑制作用表明它们具有抗炎功能。
