Enhanced production of tissue inhibitor of metalloproteinases by peripheral blood mononuclear cells of rheumatoid arthritis patients responding to methotrexate treatment.
Enhanced production of tissue inhibitor of metalloproteinases by peripheral blood mononuclear cells of rheumatoid arthritis patients responding to methotrexate treatment.
复制标题
类风湿性关节炎患者外周血单核细胞对甲氨蝶呤治疗的反应增强了金属蛋白酶组织抑制剂的产生。
作者：
M. Seitz;J. Dayer
目标
目的 确定甲氨蝶呤 (MTX) 治疗类风湿性关节炎 (RA) 患者 (a) 对循环水平和 (b) 对外周血单核细胞 (PBMNC) 离体产生基质金属蛋白酶 - 1 (MMP-1) 和金属蛋白酶 - 1 (TIMP-1) 组织抑制剂 (TIMP-1) 的影响。
方法
通过免疫分析评估来自 27 名活动性 RA 患者开始 MTX 治疗前和治疗后 3 个月以及 7 名健康受试者的 PBMNC 血清和培养上清液中 MMP-1、TIMP-1 和白细胞介素 6 (IL-6) 的循环水平、自发离体和体外产生。 MMP-1、TIMP-1 和 IL-6 的产生和血清水平与临床反应相关。
结果
RA 患者的 PBMNC 在 MTX 治疗 3 个月后显示 Paulus 指数改善 >/= 20%（应答者；n = 16），表现出离体自发 TIMP-1 的产生显着增强，这与 IL-6 合成的增强有关。相比之下，11 名疾病改善和/或进展<20% 的患者的 PBMNC 显示 TIMP-1 和 IL-6 分泌显着减少。两组中 TIMP-1 的循环水平均保持不变，而应答组的血清 IL-6 水平则有所下降。仅在极少数培养物上清液和 RA 血清中可检测到 MMP-1。此外，健康供体的 PBMNC 表明，MTX 还在体外刺激 TIMP-1 和 IL-6 释放，IL-6 部分负责诱导 TIMP-1 产生。
结论
无论是体外还是体外，MTX 治疗后 RA 患者和健康个体的 PBMNC 产生的 TIMP-1 增强与同时增强的 IL-6 释放相关，并且两者的体外产生明显与短期临床疗效相关。这可能反映了接受 MTX 治疗的 RA 患者的疾病缓解以及对异常炎症和细胞外基质周转的宿主防御机制的有利影响。
OBJECTIVE
To determine the effects of methotrexate (MTX) treatment of rheumatoid arthritis (RA) patients (a) on the circulating levels and (b) on the ex vivo production of matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinases-1 (TIMP-1) by peripheral blood mononuclear cells (PBMNC).
METHODS
Circulating levels, spontaneous ex vivo and in vitro production of MMP-1, TIMP-1 and interleukin-6 (IL-6) were assessed by immunoassays in sera and culture supernatants of PBMNC derived from 27 patients with active RA before and 3 months after beginning MTX treatment and from seven healthy subjects. The production and serum levels of MMP-1, TIMP-1 and IL-6 were correlated to the clinical response.
RESULTS
PBMNC of RA patients showing >/= 20% improvement of the Paulus index after 3 months of MTX treatment (responders; n = 16) exhibited a significantly enhanced production of spontaneous TIMP-1 ex vivo which was associated with the enhanced synthesis of IL-6. In contrast, PBMNC of 11 patients with <20% improvement and/or progression of disease showed a marked reduction of TIMP-1 and IL-6 secretion. Circulating levels of TIMP-1 remained unchanged in both groups whereas serum IL-6 levels declined in the responder group. MMP-1 was detectable only in very few culture supernatants and RA sera. Moreover, PBMNC of healthy donors revealed that MTX also stimulated TIMP-1 and IL-6 release in vitro, IL-6 being partially responsible for the induction of TIMP-1 production.
CONCLUSIONS
Both ex vivo and in vitro, the enhanced TIMP-1 production by PBMNC of RA patients and healthy individuals upon MTX treatment is associated with simultaneously enhanced IL-6 release, and enhanced ex vivo production of both is clearly associated with short-term clinical efficacy. This may reflect disease remission and favourable effects on host defence mechanisms against aberrant inflammation and extracellular matrix turnover in RA patients undergoing MTX treatment.
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DOI：
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