Deckers J G, De Haij S, van der Woude F J, van der Kooij S W, Daha M R, van Kooten C
Department of Nephrology, Leiden University Medical Center, The Netherlands.
J Am Soc Nephrol. 1998 Jul;9(7):1187-93. doi: 10.1681/ASN.V971187.
Local production of cytokines by infiltrating monocytes/macrophages and Th1 and Th2 cells is of importance in renal allograft rejection. Activated Th1 cells can produce interleukin-2 (IL-2), interferon-gamma (IFN-gamma), and tumor necrosis factor (TNF), whereas Th2 cells produce IL-4 and IL-13, which inhibit Th1 cells. Furthermore, activated T cells express the costimulatory molecule CD40-ligand. During renal allograft rejection, the chemokine RANTES is detected in both infiltrating mononuclear cells and tubular epithelium. It has been shown previously that stimulation of proximal tubular epithelial cells (PTEC) with cytokines or CD40-ligand results in production of RANTES. The present study investigates the influence of Th1 and Th2 cytokines on RANTES production by activated PTEC. RANTES was not detectable in supernatants of human PTEC stimulated with IL-2, IL-4, IL-10, or IL-13 alone. Likewise, combination of these cytokines with IL-1 alpha, IFN-gamma, or TNF-alpha, respectively, did not result in detectable RANTES production. IL-2 and IL-10 had no significant effect on RANTES production by activated PTEC. IL-4 or IL-13 in combination with IL-1 alpha + IFN-gamma or IFN-gamma + TNF-alpha resulted in a two- to fourfold augmentation of RANTES production, ranging from 2.2 +/- 0.2 to 35 +/- 2 ng/ml in different cell lines. CD40-activated PTEC stimulated with IL-4 or IL-13 produced six to ten times more RANTES (ranging from 7.9 +/- 1.9 to 62 +/- 3.5 ng/ml in different cell lines) compared with CD40-activated cells alone. Because RANTES production is augmented by IL-4 and IL-13, this study suggests that during rejection, direct cellular contact between activated Th2 cells and tubular epithelial cells amplifies the local inflammatory reaction in the kidney.
浸润的单核细胞/巨噬细胞以及Th1和Th2细胞在局部产生细胞因子，这在肾移植排斥反应中具有重要意义。活化的Th1细胞可产生白细胞介素-2（IL-2）、干扰素-γ（IFN-γ）和肿瘤坏死因子（TNF），而Th2细胞产生IL-4和IL-13，它们可抑制Th1细胞。此外，活化的T细胞表达共刺激分子CD40配体。在肾移植排斥反应期间，趋化因子RANTES在浸润的单核细胞和肾小管上皮中均有检测到。先前已表明，用细胞因子或CD40配体刺激近端肾小管上皮细胞（PTEC）会导致RANTES的产生。本研究调查了Th1和Th2细胞因子对活化的PTEC产生RANTES的影响。单独用IL-2、IL-4、IL-10或IL-13刺激人PTEC的上清液中未检测到RANTES。同样，这些细胞因子分别与IL-1α、IFN-γ或TNF-α联合使用也未导致可检测到的RANTES产生。IL-2和IL-10对活化的PTEC产生RANTES没有显著影响。IL-4或IL-13与IL-1α + IFN-γ或IFN-γ + TNF-α联合使用可使RANTES的产生增加两到四倍，在不同细胞系中范围为2.2±0.2至35±2 ng/ml。与单独的CD40活化细胞相比，用IL-4或IL-13刺激的CD40活化PTEC产生的RANTES多六到十倍（在不同细胞系中范围为7.9±1.9至62±3.5 ng/ml）。由于IL-4和IL-13可增加RANTES的产生，本研究表明在排斥反应期间，活化的Th细胞与肾小管上皮细胞之间的直接细胞接触会放大肾脏中的局部炎症反应。
