Alternative pathway complement activation induces proinflammatory activity in human proximal tubular epithelial cells
Alternative pathway complement activation induces proinflammatory activity in human proximal tubular epithelial cells
复制标题
DOI：
10.1093/ndt/12.1.51
复制
发表时间：
1997-01-01
影响因子：
6.1
通讯作者：
Camussi, G
中科院分区：
文献类型：
--
作者：
David, S;Biancone, L;Camussi, G
背景近端肾小管上皮细胞表达表面C3转化酶活性，其诱导C固定和C5 b-9膜攻击复合物（MAC）插入细胞质膜。这种现象的病理生理后果是未知的。探讨了C固定对培养的人近端肾小管上皮细胞产生炎症介质的影响。近端肾小管上皮细胞与亚溶解量的正常人血清作为C的来源孵育，但不与热灭活的人血清，表现出时间依赖性的钙内流和C-14-花生四烯酸（C-14-AA）的伴随释放。花生四烯酸动员后的类花生酸合成被研究为前列腺素E（2）的释放; Mg 2 +/EGTA（不能阻止C3-转化酶激活C）和对溴代苯甲酰甲基溴（磷脂酶A（2）抑制剂）抑制C-14-AA的动员。这些结果表明细胞外钙依赖性磷脂酶A的激活（2）。补体结合与促炎细胞因子如IL-6和TNF-α的合成相关。用C6缺陷型血清进行的实验表明，C-14-AA的释放和细胞因子的产生依赖于补体末端组分在质膜中的插入。事实上，用纯化的C6重建CG缺陷血清的正常溶血活性也恢复了C-14-AA的释放和细胞因子的产生。在体外近端肾小管细胞表面的补体激活触发促炎介质的产生，这可能有助于肾小管间质损伤的发病机制。
Background. Proximal tubular epithelial cells express a surface C3-convertase activity which induces C fixation and insertion of the C5b-9 membrane attack complex (MAC) into the cell plasma membrane. The physiopathological consequences of this phenomenon are unknown.Methods. The effect of C fixation on the production of inflammatory mediators by human proximal tubular epithelial cells in culture was explored.Results. Proximal tubular epithelial cells incubated with a sublytic amount of normal human serum as a source of C, but not with heat-inactivated human serum, showed a time-dependent calcium influx and a concomitant release of C-14-arachidonic acid (C-14-AA). Eicosanoid synthesis following the arachidonic acid mobilization was studied as prostaglandin E(2) release; Mg2+/EGTA, which did not prevent C activation by the C3-convertase, and p-bromodiphenacyl bromide, a phospholipase A(2)-inhibitor, inhibited mobilization of C-14-AA. These results suggest the activation of an extracellular Ca2+-dependent, phospholipase A(2). Complement fixation was associated with the synthesis of proinflammatory cytokines such as IL-6 and TNF-alpha. Experiments with C6-deficient sera indicated that the release of C-14-AA and the production of cytokines were dependent on the insertion of the terminal components of complement in the plasma membrane. Indeed, the reconstitution of normal haemolytic activity of CG-deficient sera with purified C6 restored also the release of C-14-AA and the production of cytokines.Conclusions. In vitro complement activation on the proximal tubular cell surface triggers the generation of proinflammatory mediators, which may potentially contribute to the pathogenesis of tubulointerstitial injury.