Tumor necrosis factor-related apoptosis-inducing ligand is a marker of kidney function and inflammation in heart and kidney transplant recipients

Background

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) was originally identified as the third member of the TNF superfamily to induce apoptosis. TRAIL is normally expressed in many human tissues including kidney. Circulating soluble TRAIL is a negative marker for inflammation and is inversely associated with the mortality risk in chronic kidney disease patients. One increasingly prevalent complication in heart transplant recipients appears to be chronic kidney disease.

Materials and Methods

The aim of the study was to assess TRAIL concentration in 136 heart transplant recipients and 80 prevalent kidney allograft recipients in relation to kidney function. Complete blood count, urea, serum lipids, fasting glucose, creatinine, NT-proBNP were studied. Soluble TRAIL, hsCR P, interleukin-6 (IL-6), von willebrand factor (vWF) were assayed using commercially available kits.

Results

Heart transplant recipients had significantly higher serum creatinine, urea, cholesterol, triglycerides, fasting glucose, white blood cell count, serum TRAIL and lower estimated glomerular filtration rate than the control group. Similar results were obtained for kidney allograft recipients. Serum TRAIL levels fell, together with decline in glomerular filtration rate in heart transplant patients. Serum TRAIL was related to age, kidney function, erythrocyte count, hemoglobin, NT-proBNP, New York Heart Association class, presence of diabetes, high-density lipoprotein (HDL), IL-6, and ejection fraction. Age and HDL turn out to be predictors of TRAIL in heart transplant recipients. In kidney transplant recipients, TRAIL was related, in univariate analysis, to age, NT-proBNP, time after transplantation, kidney function, and vWF. In multiple regression analysis, predictors of TRAIL were vWF and time after transplantation.

Conclusion

TRAIL may represent a surrogate marker of endothelial dysfunction and atherosclerosis as these processes are accelerated in heart and kidney dysfunction.     

肿瘤坏死因子相关的凋亡诱导配体基因在糖尿病大鼠肾脏细胞凋亡中的作用

目的 探讨肿瘤坏死因子(TNF)相关的凋亡诱导配体(TRAIL)基因在糖尿病大鼠肾脏细胞凋亡中的表达及其作用。方法 应用链脲佐菌素建立糖尿病大鼠模型，采用原位末端标记法和流式细胞术检测4组(对照组、糖尿病4周组、8周组和12周组)大鼠肾脏细胞凋亡情况；免疫组化和流式细胞术检测肾脏TRAIL基因及其死亡受体DR4、DR5的蛋白表达。结果 与正常对照组相比．各糖尿病组较对照组肾小球、肾小管凋亡细胞数明显增多，TRAIL、DR4、DR5的表达亦显著增强。结论 在高糖环境的诱导下．TRAIL基因及其死亡受体出现的高表达，可能部分参与了糖尿病大鼠肾脏细胞凋亡。     

白细胞介素12通过抑制survivin表达加强肿瘤坏死因子相关凋亡诱导配体诱导的肝癌细胞凋亡

目的 探讨肿瘤坏死因子相关凋亡诱导配体(TRAIL)对肝细胞癌(HCC)的治疗作用,以及TRAIL耐药的可能机制和逆转耐药方案。方法 采用原位杂交方法观察HCC与正常肝组织中TRAIL的表达差异。采用不同浓度的sTRAIL(可溶性)处理HCC细胞株及真核表达质粒pIRES-EGFP-sTRAIL转染HCC细胞株,观察sTRAIL的抑癌疗效。建立裸鼠肝癌模型,观察sTRAIL的体内抑癌作用。进一步,检测HCC中survivin的表达并采用反义寡核苷酸封闭治疗。最后,观测sTRAIL和IL-12联合抗癌效果。结果 肝癌组织DR表达量显著强于正常肝组织DR表达量。60例肝癌组织中54例不表达诱捕受体DcRl,25例不表达DcR2,而20例正常肝组织均表达DcR。两种．HCC细胞株中DcR1表达缺失。经sTRAIL(100ng/ml)处理24h,HCC细胞凋亡发生率约10％,而Jurkat细胞凋亡率达70％以上。体外pIRES-EGFP-sTRAIL转染对肝癌细胞杀伤作用不敏感。体内直接瘤体注射pIRES-EGFP-sTRAIL可对裸鼠肝癌无明显抑制作用。HCC高表达survivin,反义寡核苷酸封闭可部分逆转TRAIL耐药。IL-12使survivin表达明显下调,显著加强TRAIL对HCC细胞的杀伤作用。结论 HCC对TRAIL诱导的凋亡有耐药现象。survivin参与HCC对TRAIL的耐药机制,反义寡核苷酸封闭可部分逆转TRAIL耐药。IL-12可通过抑制siurvivin表达增强TRAIL对HCC杀癌作用。联合基因治疗(如TRAIL和IL-12基因)可能成为一种有前途HCC治疗方案。     

移植物浸润T淋巴细胞肿瘤坏死因子相关凋亡诱导配体及受体DR4和DR5表达与大鼠小肠移植急性排斥反应的相关性

目的 探讨浸润T淋巴细胞七的DR4、DR5表达同小肠移植急性排斥反应的关系.方法 将2种近交系大鼠(SD、Wistar)54只按随机配对法分为A、B、C3组.A组大鼠为对照组(18只)行虚拟手术;B组(18只)大鼠行同系小肠移植;C组(18只)大鼠行不同品系小肠移植.各组大鼠于术后5 d取移植肠样本分别做HE染色和免疫荧光双标记染色.采用免疫荧光染色、激光共聚焦技术测定各组标本浸润T淋巴细胞肿瘤坏死因相关凋亡诱导配体及DR4、DR5的表达情况.结果 A组大鼠小肠黏膜正常,B组大鼠小肠表现为免疫耐受,C组大鼠表现为急性排斥反应.C组大鼠高T淋巴细胞表达肿瘤坏死因子相关凋亡诱导配体与A、B组大鼠比较差异有统计学意义(P < 0.01);A、B组大鼠浸润T淋巴细胞DR4、DR5均呈高表达,C组大鼠呈低表达,C组大鼠与A、B组比较差异有统计学意义(P < 0.01);A、B组大鼠比较差异无统计学意义(P > 0.05).结论 急性排斥反应的发生可能与浸润T淋巴细胞DR的低表达有关.减少浸润淋巴细胞DR表达的下调,或者上调DR将有助于控制急性排斥反应,诱导免疫耐受.     

移植物浸润T淋巴细胞肿瘤坏死因子相关凋亡诱导配体及受体DR4和DR5表达与大鼠小肠移植急性排斥反应的相关性

目的 探讨浸润T淋巴细胞七的DR4、DR5表达同小肠移植急性排斥反应的关系.方法 将2种近交系大鼠(SD、Wistar)54只按随机配对法分为A、B、C3组.A组大鼠为对照组(18只)行虚拟手术;B组(18只)大鼠行同系小肠移植;C组(18只)大鼠行不同品系小肠移植.各组大鼠于术后5 d取移植肠样本分别做HE染色和免疫荧光双标记染色.采用免疫荧光染色、激光共聚焦技术测定各组标本浸润T淋巴细胞肿瘤坏死因相关凋亡诱导配体及DR4、DR5的表达情况.结果 A组大鼠小肠黏膜正常,B组大鼠小肠表现为免疫耐受,C组大鼠表现为急性排斥反应.C组大鼠高T淋巴细胞表达肿瘤坏死因子相关凋亡诱导配体与A、B组大鼠比较差异有统计学意义(P < 0.01);A、B组大鼠浸润T淋巴细胞DR4、DR5均呈高表达,C组大鼠呈低表达,C组大鼠与A、B组比较差异有统计学意义(P < 0.01);A、B组大鼠比较差异无统计学意义(P > 0.05).结论 急性排斥反应的发生可能与浸润T淋巴细胞DR的低表达有关.减少浸润淋巴细胞DR表达的下调,或者上调DR将有助于控制急性排斥反应,诱导免疫耐受.     

移植物浸润T淋巴细胞肿瘤坏死因子相关凋亡诱导配体及受体DR4和DR5表达与大鼠小肠移植急性排斥反应的相关性

目的 探讨浸润T淋巴细胞七的DR4、DR5表达同小肠移植急性排斥反应的关系.方法 将2种近交系大鼠(SD、Wistar)54只按随机配对法分为A、B、C3组.A组大鼠为对照组(18只)行虚拟手术;B组(18只)大鼠行同系小肠移植;C组(18只)大鼠行不同品系小肠移植.各组大鼠于术后5 d取移植肠样本分别做HE染色和免疫荧光双标记染色.采用免疫荧光染色、激光共聚焦技术测定各组标本浸润T淋巴细胞肿瘤坏死因相关凋亡诱导配体及DR4、DR5的表达情况.结果 A组大鼠小肠黏膜正常,B组大鼠小肠表现为免疫耐受,C组大鼠表现为急性排斥反应.C组大鼠高T淋巴细胞表达肿瘤坏死因子相关凋亡诱导配体与A、B组大鼠比较差异有统计学意义(P < 0.01);A、B组大鼠浸润T淋巴细胞DR4、DR5均呈高表达,C组大鼠呈低表达,C组大鼠与A、B组比较差异有统计学意义(P < 0.01);A、B组大鼠比较差异无统计学意义(P > 0.05).结论 急性排斥反应的发生可能与浸润T淋巴细胞DR的低表达有关.减少浸润淋巴细胞DR表达的下调,或者上调DR将有助于控制急性排斥反应,诱导免疫耐受.     

肿瘤坏死因子相关的凋亡诱导配体系统和核因子κB在糖尿病大鼠肾脏中的表达

目的探讨肿瘤坏死因子相关的凋亡诱导配体（TRAIL）系统在糖尿病肾病发生发展中的作用。方法观察TRAIL及其死亡受体4（DR4）、诱骗受体2（DcR2）和核因子KB（NF-KB）在糖尿病大鼠不同时期肾脏中的表达及分析其与肾功能的关系。将80只Wistar大鼠随机分为对照组（NC组）和糖尿病组（DM组），一侧肾切除后，腹腔注射链脲佐菌素（STZ，55mg／kg）建立糖尿病大鼠模型。在第4、8、12、16周末，随机处死各组8只大鼠，收集血液、尿液和肾组织，检测血生化指标、尿蛋白量（24h）和肥大指数等。应用荧光实时定量RT-PCR和免疫组织化学的方法检测肾皮质TRAIL及其受体DR4、DcR2和NF-KB的mRNA和蛋白的表达情况。结果各时间点DM组大鼠尿蛋白量（24h）和肥大指数（肾质量，体质量）均显著高于NC组（P〈0．05）；血白蛋白在第8周末开始显著低于NC组（P〈0．01）；Scr、BUN于第16周末显著高于NC组（P〈0．01）。DM组大鼠TRAIL及其受体DR4mRNA在第4、8及12周末时表达均显著低于NC组（P〈0．01）；第16周末时表达显著高于NC组（P〈0．01）。DM组大鼠DcR2mRNA在第4、8及12周末时表达均显著高于NC组（P〈0．01）；NF-KB的基因表达均显著高于NC组（P〈0．05）。免疫组化结果显示TRAIL及其受体DR4、DcR2主要在肾小管表达，而在肾小球和脉管系统未见表达；NF-KB在肾小球和肾小管均有表达；TRAIL及其受体和NF-KB在各组表达趋势与PCR结果一致。结论TRAIL系统作为调节细胞凋亡的一组重要因子，参与了糖尿病肾病的发生发展。     

Relationship between serum levels of tumour necrosis factor-related apoptosis-inducing ligand and the survival of Chinese peritoneal dialysis patients

Aim: Tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL) can counteract inflammation and atherosclerosis, both common causes of morbidity in peritoneal dialysis (PD) patients. We examined the relation between serum soluble TRAIL (sTRAIL) levels and the outcome of Chinese PD patients. Methods: We studied 116 new PD patients (67 males, age 56.7 ± 13.4 years). Baseline serum sTRAIL level was determined and grouped to tertiles 1 (lowest) to 3 (highest). All patients were followed for 20.9 ± 7.0 months. Results: Patient survival was 83.4%, 74.2% and 100% for tertiles 1 to 3, respectively, at 24 months (P = 0.021). Multivariate Cox regression analysis showed that serum sTRAIL level was an independent predictor of patient survival after adjusting for confounding factors (adjusted hazard ratio 0.962, 95% confidence interval [CI] 0.935–0.991, P = 0.010). Conclusion: A higher baseline serum sTRAIL level was associated with a better survival of PD patients. The detailed mechanism deserves further investigation.     

Sensitivity of prostate cells to TRAIL-induced apoptosis increases with tumor progression: DR5 and caspase 8 are key players

BACKGROUND: As advanced prostate cancers are resistant to currently available chemotherapies, we evaluated the cytotoxic effect of TNF-related apoptosis-inducing ligand (TRAIL) and characterized the involvement of its five receptors DR4, DR5, DcR1, DcR2, and osteoprotegerin (OPG) and of the death-inducing signaling complex (DISC)-forming proteins caspase 8 and c-FLIP in prostate cell lines. METHODS: We used six prostate cell lines, each corresponding to a particular stage in prostate tumorigenesis, and analyzed TRAIL sensitivity in relation to TRAIL receptors' expression. RESULTS: TRAIL sensitivity was correlated with tumor progression and DR5 expression levels and apoptosis was exclusively mediated by DR5. DcR2 was significantly more abundant in tumor cells than in non-neoplastic ones and may contribute to partial resistance to TRAIL in some prostate tumor cells. Conversely, non-tumoral cells secreted high levels of OPG, which can protect them from apoptosis. Finally, caspase 8 expression levels were as DR5 directly correlated to TRAIL sensitivity in prostate tumor cells. CONCLUSION: TRAIL-induced apoptosis is closely related to the balanced expression of its different receptors in prostate cancer cells and their modulation could be of potential clinical value for advanced tumor treatment.     

The extent of HLA‐DR expression on HLA‐DR+ Tregs allows the identification of patients with clinically relevant borderline rejection

Regulatory T cells (Tregs) were shown to be involved into the pathogenesis of acute rejection after transplantation. The suppressive activity of the total regulatory T cell pool depends on its percentage of highly suppressive HLA‐DR⁺‐Treg cells. Therefore, both the suppressive activity of the total Treg pool and the extent of HLA‐DR expression of HLA‐DR⁺‐Tregs (MFI HLA‐DR) were estimated in non transplanted volunteers, patients with end‐stage renal failure (ESRF), healthy renal transplant patients with suspicion on rejection, due to sole histological Bord‐R or sole acute renal failure (ARF), and patients with clinically relevant borderline rejection (Bord‐R and ARF). Compared to patients with only Bord‐R or only ARF, the suppressive activity of the total Treg cell pool was exclusively reduced in patients with clinically relevant Bord‐R. In parallel, the HLA‐DR MFI of the DR⁺‐Treg subset was significantly decreased in these patients, due to a significantly lower proportion of DR^high+‐Tregs, which were shown to have the highest suppressive capacity within the total Treg pool. Our findings clearly demonstrate that the determination of the HLA‐DR MFI of the HLA‐DR⁺‐Treg subset allows a highly sensitive, specific and non‐invasive discrimination between patients with clinically relevant Bord‐R (Bord and ARF) and patients with subclinical rejection or other causes of transplant failure.