Iwasaki Tsuyoshi, Imado Takehito, Kitano Sachie, Sano Hajime
Division of Rheumatology and Clinical Immunology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan.
Arthritis Res Ther. 2006;8(6):R161. doi: 10.1186/ar2068.
The tight-skin (TSK/+) mouse, a genetic model of systemic sclerosis (SSc), develops cutaneous fibrosis and defects in pulmonary architecture. Because hepatocyte growth factor (HGF) is an important mitogen and morphogen that contributes to the repair process after tissue injury, we investigated the role of HGF in cutaneous fibrosis and pulmonary architecture defects in SSc using TSK/+ mice. TSK/+ mice were injected in the gluteal muscle with either hemagglutinating virus of Japan (HVJ) liposomes containing 8 mug of a human HGF expression vector (HGF-HVJ liposomes) or a mock vector (untreated control). Gene transfer was repeated once weekly for 8 weeks. The effects of HGF gene transfection on the histopathology and expression of tumor growth factor (TGF)-beta and IL-4 mRNA in TSK/+ mice were examined. The effect of recombinant HGF on IL-4 production by TSK/+ CD4+ T cells stimulated by allogeneic dendritic cells (DCs) in vitro was also examined. Histologic analysis revealed that HGF gene transfection in TSK/+ mice resulted in a marked reduction of hypodermal thickness, including the subcutaneous connective tissue layer. The hypodermal thickness of HGF-treated TSK/+ mice was decreased two-fold to three-fold compared with untreated TSK/+ mice. However, TSK/+ associated defects in pulmonary architecture were unaffected by HGF gene transfection. HGF gene transfection significantly inhibited the expression of IL-4 and TGF-beta1 mRNA in the spleen and skin but not in the lung. We also performed a mixed lymphocyte culture and examined the effect of recombinant HGF on the generation of IL-4. Recombinant HGF significantly inhibited IL-4 production in TSK/+ CD4+ T cells stimulated by allogeneic DCs. HGF gene transfection inhibited IL-4 and TGF-beta mRNA expression, which has been postulated to have a major role in fibrinogenesis and reduced hypodermal thickness, including the subcutaneous connective tissue layer of TSK/+ mice. HGF might represent a novel strategy for the treatment of SSc.
紧皮（TSK/+）小鼠是系统性硬化症（SSc）的一种遗传模型，会出现皮肤纤维化和肺结构缺陷。由于肝细胞生长因子（HGF）是一种重要的促有丝分裂剂和形态发生素，有助于组织损伤后的修复过程，我们使用TSK/+小鼠研究了HGF在SSc皮肤纤维化和肺结构缺陷中的作用。将含有8微克人HGF表达载体的日本血凝病毒（HVJ）脂质体（HGF-HVJ脂质体）或空载体（未处理对照）注射到TSK/+小鼠的臀肌中。每周重复基因转移一次，共8周。检测了HGF基因转染对TSK/+小鼠组织病理学以及肿瘤生长因子（TGF）-β和IL-4 mRNA表达的影响。还检测了重组HGF对体外同种异体树突状细胞（DCs）刺激的TSK/+ CD4+ T细胞产生IL-4的影响。组织学分析显示，TSK/+小鼠中的HGF基因转染导致皮下厚度显著降低，包括皮下结缔组织层。与未处理的TSK/+小鼠相比，HGF处理的TSK/+小鼠的皮下厚度降低了两倍至三倍。然而，TSK/+相关的肺结构缺陷不受HGF基因转染的影响。HGF基因转染显著抑制了脾脏和皮肤中IL-4和TGF-β1 mRNA的表达，但在肺中没有。我们还进行了混合淋巴细胞培养，并检测了重组HGF对IL-4产生的影响。重组HGF显著抑制了同种异体DCs刺激的TSK/+ CD4+ T细胞中IL-4的产生。HGF基因转染抑制了IL-4和TGF-β mRNA的表达，据推测这在纤维蛋白生成中起主要作用，并减少了TSK/+小鼠包括皮下结缔组织层在内的皮下厚度。HGF可能代表了一种治疗SSc的新策略。
