Rathanaswami P, Hachicha M, Sadick M, Schall T J, McColl S R
Centre de Recherche en Inflammation, Immunologie et Rhumatologie, Université Laval, Québec, Canada.
J Biol Chem. 1993 Mar 15;268(8):5834-9.
A chronic inflammatory disease may be characterized by an accumulation of activated leukocytes at the site of inflammation. Since the chemokine RANTES may play an active role in recruiting leukocytes into inflammatory sites, we investigated the ability of cultured human synovial fibroblasts isolated from patients suffering from rheumatoid arthritis to produce this chemokine and compared its regulation to that of the closely related chemokine gene, interleukin-8 (IL-8). In unstimulated synovial fibroblasts, the expression of mRNA for both chemokines was undetectable, but was increased in both a time- and dose-dependent manner upon stimulation with the monokines tumor necrosis factor alpha (TNF alpha) and interleukin-1 beta (IL-1 beta). Preincubation of the cells with cycloheximide "superinduced" the level of IL-8 mRNA stimulated by TNF alpha and IL-1 beta and RANTES mRNA stimulated by IL-1 beta, but decreased the expression of RANTES mRNA in response to TNF alpha. In addition, differential regulation of these genes was noted when synovial fibroblasts were stimulated with a combination of cytokines. IL-4 down-regulated and IFN gamma enhanced the TNF alpha- and IL-1 beta-induced increase in RANTES mRNA, whereas the induction of IL-8 mRNA by TNF alpha or IL-1 beta was inhibited by IFN gamma and augmented by IL-4. Moreover, a combination of TNF alpha and IL-1 beta synergistically induced IL-8 mRNA expression, whereas under the same conditions, the level of expression of RANTES mRNA was less than that induced by TNF alpha alone. These observations were also reflected at the level of chemokine secretion. These studies demonstrate that by expressing the chemokines RANTES and IL-8, synovial fibroblasts may participate in the ongoing inflammatory process in rheumatoid arthritis. In addition, the observation that these chemokine genes are differentially regulated, depending upon the presence of different cytokines, indicates that the type of cellular infiltrate and the progress of the inflammatory disease is likely to depend on the relative levels of stimulatory and inhibitory cytokines.
慢性炎症性疾病的特征可能是炎症部位有活化白细胞的积聚。由于趋化因子RANTES可能在将白细胞募集到炎症部位中发挥积极作用，我们研究了从类风湿性关节炎患者分离出的培养人滑膜成纤维细胞产生这种趋化因子的能力，并将其调节与密切相关的趋化因子基因白细胞介素-8（IL-8）的调节进行了比较。在未受刺激的滑膜成纤维细胞中，两种趋化因子的mRNA表达均无法检测到，但在用单核因子肿瘤坏死因子α（TNFα）和白细胞介素-1β（IL-1β）刺激后，其表达呈时间和剂量依赖性增加。用放线菌酮对细胞进行预孵育会“超诱导”TNFα和IL-1β刺激的IL-8 mRNA水平以及IL-1β刺激的RANTES mRNA水平，但会降低RANTES mRNA对TNFα的反应性表达。此外，当用细胞因子组合刺激滑膜成纤维细胞时，注意到了这些基因的差异调节。IL-4下调而IFNγ增强TNFα和IL-1β诱导的RANTES mRNA增加，而TNFα或IL-1β诱导的IL-8 mRNA被IFNγ抑制并被IL-4增强。此外，TNFα和IL-1β的组合协同诱导IL-8 mRNA表达，而在相同条件下，RANTES mRNA的表达水平低于单独由TNFα诱导的水平。这些观察结果也反映在趋化因子分泌水平上。这些研究表明，滑膜成纤维细胞通过表达趋化因子RANTES和IL-8，可能参与类风湿性关节炎中正在进行的炎症过程。此外，这些趋化因子基因根据不同细胞因子的存在而受到差异调节的观察结果表明，细胞浸润的类型和炎症性疾病的进展可能取决于刺激和抑制细胞因子的相对水平。
