RANTES/CCL5 Induces Collagen Degradation by Activating MMP-1 and MMP-13 Expression in Human Rheumatoid Arthritis Synovial Fibroblasts.
RANTES/CCL5 Induces Collagen Degradation by Activating MMP-1 and MMP-13 Expression in Human Rheumatoid Arthritis Synovial Fibroblasts.
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DOI：
10.3389/fimmu.2017.01341
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发表时间：
2017
影响因子：
7.3
通讯作者：
Ahmed S
中科院分区：
文献类型：
--
作者：
Agere SA;Akhtar N;Watson JM;Ahmed S
调节活化的正常T细胞表达和分泌的（RANTES）/CC配体5（CCL 5）通过促进白细胞浸润参与类风湿关节炎（RA）的发病机制，然而，其在RA中的其他病理功能尚未完全确定。在本研究中，我们评估了RANTES/CCL 5对组织降解酶基质金属蛋白酶-1（MMP-1）和MMP-13表达的影响及其对RA滑膜成纤维细胞（RASFs）进行性关节损伤的作用。我们的研究结果表明，RANTES/CCL 5剂量依赖性地诱导MMP-1和MMP-13在单层和三维（3D）微团的人RASFs的表达，这与胶原酶活性的增加。在RASF中观察到RANTES/CCL 5的这种激活，但在骨关节炎SF（OASFs）中未观察到。对信号传导事件的评估表明，RANTES/CCL 5选择性地激活PKCδ、JNK和ERK蛋白，以诱导人RASF中MMP的表达。用功能性拮抗剂（Met-RANTES）或肝素酶III（一种选择性抑制硫酸乙酰肝素蛋白聚糖（HSPG）的酶）预处理完全废除RANTES/CCL 5诱导的MMP-1和MMP-13表达。有趣的是，使用小干扰RNA方法抑制RANTES/CCL 5降低了白细胞介素-1 β（IL-1β）诱导MMP-1和MMP-13表达的能力，表明其在组织重塑中的介导作用。在抑制剂研究中，仅选择性抑制HSPGs或PKCδ、ERK和JNK显著抑制RANTES/CCL 5诱导的MMP-1和MMP-13的产生。圆二色光谱结果表明，暴露于RANTES/CCL 5刺激的RASFs的条件培养基后，胶原三螺旋结构发生降解，这被广谱MMP抑制剂（GM 6001）逆转。提示RANTES/CCL 5不仅通过HSPGs和/或PKCδ-JNK/ERK途径上调MMP-1和MMP-13的表达，而且介导IL-1β诱导的MMP-1和MMP-13的表达。
Regulated on activation, normal T expressed, and secreted (RANTES)/CC ligand 5 (CCL5) participates in rheumatoid arthritis (RA) pathogenesis by facilitating leukocyte infiltration, however, its other pathological functions are not fully defined in RA. In the present study, we evaluated the effect of RANTES/CCL5 on tissue degrading enzymes matrix metalloproteinase-1 (MMP-1) and MMP-13 expression and its contribution to the progressive joint damage by RA synovial fibroblasts (RASFs). Our results showed that RANTES/CCL5 dose dependently induced MMP-1 and MMP-13 expression in monolayers and three-dimensional (3D) micromass of human RASFs, which correlated with an increase in collagenase activity. This activation by RANTES/CCL5 was observed in RASF, but not in osteoarthritis SFs (OASFs). Evaluation of the signaling events showed that RANTES/CCL5 selectively activated PKCδ, JNK, and ERK proteins to induce MMP expression in human RASFs. Pretreatment with a functional antagonist (Met-RANTES) or heparinase III [an enzyme that selectively digests heparan sulfate proteoglycans (HSPGs)] completely abrogated RANTES/CCL5-induced MMP-1 and MMP-13 expression. Interestingly, the inhibition of RANTES/CCL5 using small-interfering RNA approach reduced the ability of interleukin-1β (IL-1β) to induce MMP-1 and MMP-13 expression, asserting its mediatory role in tissue remodeling. In the inhibitor study, only the selective inhibition of HSPGs or PKCδ, ERK, and JNK markedly inhibited RANTES/CCL5-induced MMP-1 and MMP-13 production. Circular dichroism spectroscopy results demonstrated the degradation of collagen triple-helical structure upon exposure to the conditioned media from RANTES/CCL5 stimulated RASFs, which was reverted by a broad-spectrum MMP inhibitor (GM6001). These findings suggest that RANTES/CCL5 not only upregulates MMP-1 and MMP-13 expression by partly utilizing HSPGs and/or PKCδ-JNK/ERK pathways but also mediates IL-1β-induced MMP-1 and MMP-13 expression.
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影响因子：
5.5
作者：
Catrina, AI;Lampa, J;Ulfgren, AK
通讯作者：
Ulfgren, AK
影响因子：
4.4
作者：
Sabeh, Farideh;Fox, David;Weiss, Stephen J.
通讯作者：
Weiss, Stephen J.
JAK抑制剂tofacitinib抑制类风湿关节炎中的滑膜JAK1-STAT信号传导。
影响因子：
27.4
作者：
Boyle DL;Soma K;Hodge J;Kavanaugh A;Mandel D;Mease P;Shurmur R;Singhal AK;Wei N;Rosengren S;Kaplan I;Krishnaswami S;Luo Z;Bradley J;Firestein GS
通讯作者：
Firestein GS
DOI：
10.1124/jpet.102.048611
发表时间：
2003-06-01
影响因子：
3.5
作者：
Ahmed, S;Rahman, A;Haqqi, TM
通讯作者：
Haqqi, TM
影响因子：
5.5
作者：
Noh, E. -M.;Kim, J. -S.;Lee, Y. -R.
通讯作者：
Lee, Y. -R.