Burger D, Rezzonico R, Li J M, Modoux C, Pierce R A, Welgus H G, Dayer J M
University Hospital of Geneva, Switzerland.
Arthritis Rheum. 1998 Oct;41(10):1748-59. doi: 10.1002/1529-0131(199810)41:10<1748::AID-ART7>3.0.CO;2-3.
To determine whether direct cell-cell contact with stimulated T lymphocytes (a) differentially modulates the production of interstitial collagenase (matrix metalloproteinase 1 [MMP-1]) and tissue inhibitor of metalloproteinases 1 (TIMP-1) on human synoviocytes and dermal fibroblasts, and (b) induces the production of prostaglandin E2 (PGE2); and to identify the membrane-associated factors on T cell surfaces involved in these mechanisms.
Dermal fibroblasts and fibroblast-like synovial cells (synoviocytes) were cultured with fixed T cells, isolated plasma membranes from T cells, interleukin-1beta (IL-1beta; 250 pg/ml), or transforming growth factor beta (TGFbeta; 5 ng/ml). Culture supernatants were assayed for the production of MMP-1, TIMP-1, and PGE2. The expression of MMP-1 and TIMP-1 messenger RNA was analyzed by Northern blot of total fibroblast RNA.
Membranes of stimulated T cells, i.e., human peripheral blood T lymphocytes (PBTL) and the human T cell line HUT-78, induced the production of PGE2 and MMP-1 on both synoviocytes and dermal fibroblasts. TIMP-1 production was enhanced upon contact with PBTL stimulated for short periods of time (2-4 hours) but not for longer periods. Similar results were obtained with CD4+ and CD8+ synovial tissue T cell clones (TCCs), which induced the production of TIMP-1 by fibroblasts when stimulated for short (2-4 hours), but not long, periods of time. This time dependency was not observed with HUT-78 cells. The production of MMP-1 by fibroblasts and synoviocytes upon cellular contact with stimulated T cells was higher than that induced by an optimum concentration of IL-1beta, whereas the production of PGE2 was equivalent or slightly lower. Cell membrane-associated IL-1alpha and tumor necrosis factor a, but not CD69, CD40 ligand, or CD11b, were involved in the induction of MMP-1 and PGE2 production, as shown by blockade experiments using monoclonal antibodies and cytokine antagonists.
Synovial tissue TCCs and PBTL stimulated for long periods of time trigger the production of PGE2 and MMP-1, but not TIMP-1, in synoviocytes and dermal fibroblasts, thus inducing an imbalance between the metalloenzyme and its inhibitor. These results demonstrate that T cells may affect fibroblast and synoviocyte functions directly (i.e., by contact activation) and indirectly (i.e., by activation of cytokine production in monocyte/macrophages, which in turn, trigger stromal cell functions). Since the production of MMPs in monocyte/macrophages is also induced upon contact with stimulated T cells, our results strongly suggest that contact of synovial cells with chronically stimulated T lymphocytes favors matrix catabolism. By analogy, this mechanism may trigger tissue destruction in vivo and, thus, may potentiate tissue destruction in chronic inflammatory diseases such as RA.
确定与活化的T淋巴细胞直接的细胞 - 细胞接触是否（a）对人滑膜细胞和真皮成纤维细胞中间质胶原酶（基质金属蛋白酶1 [MMP - 1]）和金属蛋白酶组织抑制剂1（TIMP - 1）的产生有不同的调节作用，以及（b）诱导前列腺素E2（PGE2）的产生；并鉴定参与这些机制的T细胞表面的膜相关因子。
将真皮成纤维细胞和类成纤维滑膜细胞（滑膜细胞）与固定的T细胞、从T细胞分离的质膜、白细胞介素 - 1β（IL - 1β；250 pg/ml）或转化生长因子β（TGFβ；5 ng/ml）一起培养。检测培养上清液中MMP - 1、TIMP - 1和PGE2的产生。通过对成纤维细胞总RNA进行Northern印迹分析MMP - 1和TIMP - 1信使RNA的表达。
活化的T细胞的质膜，即人外周血T淋巴细胞（PBTL）和人T细胞系HUT - 78，可诱导滑膜细胞和真皮成纤维细胞产生PGE2和MMP - 1。与短期（2 - 4小时）而非长期活化的PBTL接触后，TIMP - 1的产生增加。CD4 +和CD8 +滑膜组织T细胞克隆（TCC）也得到类似结果，短期（2 - 4小时）而非长期活化的TCC可诱导成纤维细胞产生TIMP - 1。HUT - 78细胞未观察到这种时间依赖性。成纤维细胞和滑膜细胞与活化的T细胞细胞接触后MMP - 1的产生高于最佳浓度IL - 1β诱导的水平，而PGE2的产生相当或略低。如使用单克隆抗体和细胞因子拮抗剂的阻断实验所示，细胞膜相关的IL - 1α和肿瘤坏死因子α，而非CD69、CD40配体或CD11b，参与MMP - 1和PGE2产生的诱导。
长期活化的滑膜组织TCC和PBTL可触发滑膜细胞和真皮成纤维细胞产生PGE2和MMP - 1，但不产生TIMP - 1，从而导致金属酶及其抑制剂之间的失衡。这些结果表明，T细胞可能直接（即通过接触激活）和间接（即通过激活单核细胞/巨噬细胞中的细胞因子产生，进而触发基质细胞功能）影响成纤维细胞和滑膜细胞功能。由于单核细胞/巨噬细胞中MMPs的产生在与活化的T细胞接触后也被诱导，我们的结果强烈表明滑膜细胞与慢性活化的T淋巴细胞接触有利于基质分解代谢。类似地，这种机制可能在体内触发组织破坏，因此可能增强诸如类风湿性关节炎等慢性炎症疾病中的组织破坏。
