Phan S H, Gharaee-Kermani M, McGarry B, Kunkel S L, Wolber F W
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109.
J Immunol. 1992 Jul 1;149(1):103-6.
Recent studies suggest that transforming growth factor-beta (TGF-beta) production is up-regulated at sites of tissue injury, inflammation and repair, or fibrosis. Endothelial cells represent a potentially important in vivo source of TGF-beta; however, the identity of endogenous modulators of TGF-beta production by these cells remains unclear. To address this issue, the effects of the cytokines, IL-1 beta, and TNF-alpha on TGF-beta production by rat pulmonary artery endothelial cells were examined. Conditioned media from cells treated with 0 to 20 ng/ml IL-1 beta and/or TNF-alpha were assayed for TGF-beta activity using a mink lung epithelial cell line. The results show that rat pulmonary artery endothelial cells secreted undetectable amounts of active TGF-beta in the absence of cytokines. However, upon acidification of the conditioned media before assay, a time-dependent increase in TGF-beta activity was noted in media from both untreated and cytokine-treated cells. However, both IL-1 beta and TNF-alpha treatment caused the secretion of significantly greater amounts of TGF-beta activity than control cells, in a dose-dependent manner, with maximal response obtained at cytokine doses of greater than 10 ng/ml. At equivalent doses of cytokine tested, the magnitude of the response was significantly greater with IL-1 beta. These responses were paralleled by increases in steady state mRNA levels for TGF-beta 1. Addition of both cytokines resulted in a synergistic response. Synergism with IL-1 beta was also noted with the fibrogenic agent bleomycin. Kinetic studies indicated that a minimum of 4 h of treatment with either IL-1 beta or TNF-alpha was required for detection of significant increases in either secreted TGF-beta activity or steady state TGF-beta 1 mRNA levels. Thus, endothelial cells could play a role in various TGF-beta-dependent processes in vivo, in situations wherein IL-1 beta and/or TNF-alpha may be present at comparable concentrations.
近期研究表明，在组织损伤、炎症、修复或纤维化部位，转化生长因子-β（TGF-β）的产生会上调。内皮细胞是TGF-β潜在的重要体内来源；然而，这些细胞产生TGF-β的内源性调节因子的身份仍不清楚。为了解决这个问题，研究了细胞因子白细胞介素-1β（IL-1β）和肿瘤坏死因子-α（TNF-α）对大鼠肺动脉内皮细胞产生TGF-β的影响。使用貂肺上皮细胞系对用0至20 ng/ml IL-1β和/或TNF-α处理的细胞的条件培养基进行TGF-β活性测定。结果表明，在没有细胞因子的情况下，大鼠肺动脉内皮细胞分泌的活性TGF-β量无法检测到。然而，在测定前对条件培养基进行酸化后，未处理和细胞因子处理的细胞培养基中TGF-β活性均呈现出时间依赖性增加。然而，IL-1β和TNF-α处理均导致分泌的TGF-β活性比对照细胞显著增加，呈剂量依赖性，在细胞因子剂量大于10 ng/ml时获得最大反应。在测试的等效细胞因子剂量下，IL-1β的反应幅度明显更大。这些反应伴随着TGF-β1稳态mRNA水平的增加。两种细胞因子的添加导致协同反应。与致纤维化剂博来霉素一起也观察到与IL-1β的协同作用。动力学研究表明，用IL-1β或TNF-α处理至少4小时才能检测到分泌的TGF-β活性或稳态TGF-β1 mRNA水平的显著增加。因此，在体内IL-1β和/或TNF-α可能以相当浓度存在的情况下，内皮细胞可能在各种TGF-β依赖性过程中发挥作用。
