Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong, University of Science and Technology, Wuhan, China.
J Biomed Sci. 2017 Sep 19;24(1):77. doi: 10.1186/s12929-017-0383-3.
Several tumour necrosis factor (TNF) based therapeutics have already been approved for human use and several others are emerging. Therefore, we determined the mRNA expression levels of the TNF superfamily ligands (TNFSF) - e.g. TNF-α, lymphotoxin (LT)-α, LT-β, Fas-L (CD95-L), TNF-related apoptosis-inducing ligand (TRAIL), TNF-related weak inducer of apoptosis (TWEAK), 4-1BBL, OX40-L (CD252) and amyloid precursor protein (APP) in healthy human and mouse solid organs.
We used quantitative real time-PCR to analyse mRNA expression levels of TNFSF ligands. Murine models of acute ischemic renal injury, chronic oxalate nephropathy, and immune complex glomerulonephritis were used. Renal injury was assessed by PAS staining, and infiltrating immune cells were analysed by immunohistochemistry. Data was analysed using non-parametric ANOVA (non-parametric; Kruskal-Wallis test).
We observed significant differences in the mRNA expression levels of TNFSF ligands in human and mouse solid organs. Furthermore, we determined their mRNA expressions during acute and chronic kidney injuries in mice. Our data demonstrate that the mRNA expression levels of TNFSF vary depending on the type of tissue injury - for example, acute ischemic renal injury, chronic crystalline nephropathy, and immune complex glomerulonephritis. In addition, we observed that mRNA expressions of TNFSF ligands are differentially regulated during the course of a transient ischemic renal injury (IRI) and chronic kidney modelling. We observed that TNF-α, LT-β, and 4-1BBL were significantly upregulated during the progression of IRI and crystal-induced chronic kidney disease (CKD), whereas only 4-1BBL and TNF-α were significantly upregulated and LT-β was significantly downregulated during the progression of immune complex glomerulonephritis. The mRNA expression of Fas-L was higher during IRI whereas it decreased in a time dependent manner during the progression of crystal-induced CKD.
We conclude that the injury- and species-specific differences of TNFSF ligands must be considered in order to avoid the misinterpretation and wrong conclusions during data extrapolation between species.
已有几种肿瘤坏死因子（TNF）为基础的治疗药物被批准用于人类，还有几种正在出现。因此，我们确定了 TNF 超家族配体（TNFSF）的 mRNA 表达水平，例如 TNF-α、淋巴毒素（LT）-α、LT-β、Fas-L（CD95-L）、TNF 相关凋亡诱导配体（TRAIL）、TNF 相关弱凋亡诱导配体（TWEAK）、4-1BBL、OX40-L（CD252）和淀粉样前体蛋白（APP）在健康的人类和小鼠实体器官中的表达。
我们使用定量实时 PCR 分析 TNFSF 配体的 mRNA 表达水平。使用急性缺血性肾损伤、慢性草酸盐肾病和免疫复合物肾小球肾炎的小鼠模型。通过 PAS 染色评估肾损伤，通过免疫组织化学分析浸润的免疫细胞。使用非参数方差分析（非参数；Kruskal-Wallis 检验）分析数据。
我们观察到人类和小鼠实体器官中 TNFSF 配体的 mRNA 表达水平存在显著差异。此外，我们在小鼠的急性和慢性肾损伤中确定了它们的 mRNA 表达。我们的数据表明，TNFSF 的 mRNA 表达水平取决于组织损伤的类型，例如急性缺血性肾损伤、慢性结晶肾病和免疫复合物肾小球肾炎。此外，我们观察到 TNFSF 配体的 mRNA 表达在短暂缺血性肾损伤（IRI）和慢性肾脏模型形成过程中存在差异调节。我们观察到 TNF-α、LT-β 和 4-1BBL 在 IRI 和晶体诱导的慢性肾病（CKD）进展过程中显著上调，而只有 4-1BBL 和 TNF-α在免疫复合物肾小球肾炎进展过程中显著上调，LT-β显著下调。Fas-L 的 mRNA 表达在 IRI 期间较高，而在晶体诱导的 CKD 进展过程中呈时间依赖性降低。
我们得出结论，在跨物种数据外推时，必须考虑 TNFSF 配体的损伤和物种特异性差异，以避免误解和错误结论。
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