Sasaki Hiroyoshi, Sato Tsutomu, Yamauchi Naofumi, Okamoto Tetsuro, Kobayashi Daisuke, Iyama Satoshi, Kato Junji, Matsunaga Takuya, Takimoto Rishu, Takayama Tetsuji, Kogawa Katsuhisa, Watanabe Naoki, Niitsu Yoshiro
Department of Internal Medicine (Section 4) and Clinical Diagnosis Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Sapporo 060-8543, Japan.
J Immunol. 2002 May 15;168(10):5178-83. doi: 10.4049/jimmunol.168.10.5178.
With most immunological reactions, tissue fibrosis, collagen overproduction caused by immune cytokines, is inevitably associated. Among the various immune cytokines, heat shock protein 47 (HSP47) is a procollagen-specific molecular chaperon and is essential for secretion of procollagen from cells. Induction of HSP47 by TGF-beta has been previously reported in rat skeletal myoblasts and mouse osteoblasts, but not in human diploid fibroblasts. As for IL-1beta, its effect on HSP47 has not been elucidated. In the present study, using human embryonic lung fibroblast cells, we first disclosed that both TGF-beta and IL-1beta induced HSP47 synthesis. We then revealed that the binding of the heat shock element (HSE) by heat shock transcription factor 1 (HSF1) was enhanced by both cytokines. We further demonstrated that trimer formation of HSF1, which is essential for its binding to HSE, was induced by these cytokines. The enhancement of HSP47 synthesis and their trimer formation of HSF1 were augmented by using a combination of both cytokines. Collectively, TGF- beta and IL-1beta were found to induce trimer formation of HSF1 which in turn bound to HSE of HSP47, resulting in the enhancement of HSP47 expression. Thus, HSP47 could well be a good candidate for molecular targeting in controlling tissue fibrosis, given that both principal fibrinogenetic cytokines (TGF-beta, IL-1beta) are commonly involved in its induction through HSF1 trimerization.
在大多数免疫反应中，组织纤维化（由免疫细胞因子引起的胶原蛋白过度产生）不可避免地与之相关。在各种免疫细胞因子中，热休克蛋白47（HSP47）是一种前胶原特异性分子伴侣，对前胶原从细胞中分泌至关重要。先前已报道在大鼠骨骼肌成肌细胞和小鼠成骨细胞中，TGF-β可诱导HSP47，但在人二倍体成纤维细胞中未观察到。至于IL-1β，其对HSP47的影响尚未阐明。在本研究中，我们使用人胚胎肺成纤维细胞，首先发现TGF-β和IL-1β均可诱导HSP47的合成。然后我们发现，热休克转录因子1（HSF1）与热休克元件（HSE）的结合在两种细胞因子作用下均得到增强。我们进一步证明，这些细胞因子可诱导对HSE结合至关重要的HSF1三聚体形成。两种细胞因子联合使用可增强HSP47的合成及其诱导的HSF1三聚体形成。总体而言，发现TGF-β和IL-1β可诱导HSF1三聚体形成，进而与HSP47的HSE结合，导致HSP47表达增强。因此，鉴于两种主要的纤维生成细胞因子（TGF-β、IL-1β）通常通过HSF1三聚化共同参与HSP47的诱导，HSP47很可能是控制组织纤维化分子靶向治疗的良好候选者。
