Yard B A, Pancham R R, Paape M E, Daha M R, van Es L A, van der Woude F J
Department of Nephrology, University Hospital Leiden, The Netherlands.
Kidney Int. 1993 Aug;44(2):352-8. doi: 10.1038/ki.1993.251.
In this study we investigated the effect of immunosuppressive drugs on the interleukin-1 alpha (IL-1 alpha) enhanced tumor necrosis factor alpha (TNF alpha) production by proximal tubular epithelial cells (PTEC). Under basal conditions cultured PTEC produce between 0 to 390 pg/ml/10(5) cells of TNF alpha. Upon stimulation with IL-1 alpha an enhancement of TNF alpha production was seen in each cell line tested, ranging from 230 to 2424 pg/ml/10(5) cells. The presence of cyclosporin A (CsA) during stimulation with IL-1 alpha inhibited the enhanced TNF alpha production in a dose dependent fashion, with a maximal inhibition of 90% at a concentration of 250 ng/ml. Inhibition was at the level of mRNA as could be demonstrated by Northern blot analysis. FK506, corticosteroids and rapamycin also inhibited TNF alpha production in a dose dependent fashion, although not as effectively as CsA. Two corticosteroids were tested for their inhibitory effect on TNF alpha production. It was found that dexamethasone at a concentration of 10 ng/ml inhibited TNF alpha production for almost 40%. A 100-fold higher concentration of hydrocortisone was necessary to yield similar inhibition. The effect of rapamycin on the IL-1 alpha enhanced TNF alpha production differed from the effect of CsA. While CsA induced a maximal inhibition of 90%, rapamycin only induced a maximal inhibition of 37%, and even less inhibition at higher concentrations of the drug. The presence of the various drugs was essential for their inhibitory effect, because removal of the drug from the PTEC by washing immediately resulted in loss of inhibition. Combinations of CsA and FK506 or rapamycin were not additive.(ABSTRACT TRUNCATED AT 250 WORDS)
在本研究中，我们调查了免疫抑制药物对近端肾小管上皮细胞（PTEC）中白细胞介素-1α（IL-1α）增强肿瘤坏死因子α（TNFα）产生的影响。在基础条件下，培养的PTEC产生的TNFα为0至390 pg/ml/10⁵个细胞。在用IL-1α刺激后，在所测试的每个细胞系中都观察到TNFα产生增强，范围为230至2424 pg/ml/10⁵个细胞。在IL-1α刺激期间，环孢素A（CsA）的存在以剂量依赖方式抑制TNFα产生的增强，在浓度为250 ng/ml时最大抑制率为90%。如Northern印迹分析所示，抑制作用发生在mRNA水平。FK506、皮质类固醇和雷帕霉素也以剂量依赖方式抑制TNFα产生，尽管不如CsA有效。测试了两种皮质类固醇对TNFα产生的抑制作用。发现浓度为10 ng/ml的地塞米松抑制TNFα产生近40%。需要高100倍的氢化可的松浓度才能产生类似的抑制作用。雷帕霉素对IL-1α增强的TNFα产生的作用与CsA不同。虽然CsA诱导的最大抑制率为90%，但雷帕霉素仅诱导最大抑制率为37%，并且在更高药物浓度下抑制作用更小。各种药物的存在对其抑制作用至关重要，因为通过洗涤立即从PTEC中去除药物会导致抑制作用丧失。CsA与FK506或雷帕霉素的组合没有相加作用。（摘要截短为250字）
