Takami Yoichiro, Motoki Takahiro, Yamamoto Itaru, Gohda Eiichi
Department of Immunochemistry, Faculty of Pharmaceutical Sciences, Okayama University, Tsushima-naka, Okayama 700-8530, Japan.
Biochem Biophys Res Commun. 2005 Feb 4;327(1):212-7. doi: 10.1016/j.bbrc.2004.11.144.
Hepatocyte growth factor (HGF) is one of the vital factors for wound healing. HGF expression markedly increases in wounded skin and is mainly localized in dermal fibroblasts. HGF expression level in human dermal fibroblasts in vitro, however, is low and thus may be stimulated by some factors in the process of wound healing. Candidates of the factors are inflammatory cytokines released by polymorphonuclear and mononuclear cells infiltrating the wounded area, but HGF production in human dermal fibroblasts is only slightly induced by interleukin (IL)-1, tumor necrosis factor (TNF)-alpha or interferon (IFN)-gamma. We here report that a combination of IL-1beta and IFN-gamma or a combination of TNF-alpha and IFN-gamma very markedly induced HGF production. The synergistic effect of the former was more marked than that of the latter. Synergistic effects of IL-1beta and IFN-gamma were observed at more than 10 pg/ml and 10 IU/ml, respectively, and were detectable as early as 12 h after addition. Neither IFN-alpha nor IFN-beta was able to replace IFN-gamma. HGF mRNA expression was also synergistically upregulated by IL-1beta and IFN-gamma. IL-1beta plus IFN-gamma-induced synergistic production of HGF was potently inhibited by treatment of cells with the extracellular signal-regulated kinase (ERK) kinase inhibitor PD98059 and the p38 inhibitor SB203580 but not by the c-Jun N-terminal kinase (JNK) inhibitor SP600125. Taken together, our results indicate that a combination of IL-1beta and IFN-gamma synergistically induced HGF production in human dermal fibroblasts and suggest that activation of ERK and p38 but not of JNK is involved in the synergistic effect.
肝细胞生长因子（HGF）是伤口愈合的重要因子之一。HGF在受伤皮肤中的表达显著增加，且主要定位于真皮成纤维细胞。然而，人真皮成纤维细胞在体外的HGF表达水平较低，因此在伤口愈合过程中可能受到某些因素的刺激。这些因素的候选者是浸润伤口区域的多形核细胞和单核细胞释放的炎性细胞因子，但人真皮成纤维细胞中HGF的产生仅受到白细胞介素（IL）-1、肿瘤坏死因子（TNF）-α或干扰素（IFN）-γ的轻微诱导。我们在此报告，IL-1β和IFN-γ的组合或TNF-α和IFN-γ的组合非常显著地诱导了HGF的产生。前者的协同作用比后者更显著。IL-1β和IFN-γ的协同作用分别在超过10 pg/ml和10 IU/ml时观察到，并且在添加后12小时就可检测到。IFN-α和IFN-β都不能替代IFN-γ。HGF mRNA表达也被IL-1β和IFN-γ协同上调。用细胞外信号调节激酶（ERK）激酶抑制剂PD98059和p38抑制剂SB203580处理细胞可有效抑制IL-1β加IFN-γ诱导的HGF协同产生，但c-Jun氨基末端激酶（JNK）抑制剂SP600125则无此作用。综上所述，我们的结果表明，IL-1β和IFN-γ的组合协同诱导人真皮成纤维细胞产生HGF，并提示ERK和p38而非JNK的激活参与了协同作用。
