Role of Placenta Growth Factor and Its Receptor flt-1 in Rheumatoid Inflammation A Link Between Angiogenesis and Inflammation
Role of Placenta Growth Factor and Its Receptor flt-1 in Rheumatoid Inflammation A Link Between Angiogenesis and Inflammation
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DOI：
10.1002/art.24289
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发表时间：
2009-02-01
影响因子：
--
通讯作者：
Kim, Wan-Uk
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文献类型：
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作者：
Yoo, Seung-Ah;Yoon, Hyung-Ju;Kim, Wan-Uk
Objective.目的探讨胎盘生长因子（PlGF）及其特异性受体flt-1在类风湿关节炎（RA）炎症过程中的直接作用。免疫组化法检测类风湿关节炎滑膜组织中PIGF和flt-1的表达。酶联免疫吸附测定用于测定单核细胞或滑膜细胞的培养上清液中PIGF、肿瘤坏死因子α（TNF α）和白细胞介素-6（IL-6）的浓度。FLT-1。通过流式细胞术分析单核细胞中的表达水平。用Ⅱ型胶原（CII）免疫小鼠或注射抗CII抗体诱导小鼠实验性关节炎。类风湿关节炎患者滑膜中PIGF高表达，其主要来源为成纤维细胞样滑膜细胞（FLS）。当用1 L-1 β刺激时，RA患者的FLS产生的PIGF量高于骨关节炎患者的FLS。外源性PlGF通过钙调神经磷酸酶依赖性途径特异性地增加RA患者（而不是健康对照者）单核细胞中TNF α和IL-6的产生。对PlGF的反应与RA单核细胞上flt-1表达的增加相关，这可以由IL-1 β和TNF α诱导。一种新的抗flt-1六肽GNQWFI消除了PIGF诱导的TNF α和IL-6产生的增加，并且还抑制了小鼠中CII诱导的关节炎和血清IL-6浓度。此外，基因切除PIGF可预防小鼠中抗CII抗体诱导的关节炎的发展。我们的数据表明，PIGF和flt-1的表达增强可能会导致类风湿性炎症，触发生产的促炎细胞因子。使用新型抗flt-1肽GNQWFI可能是治疗RA的有效策略。
Objective. To investigate the direct effects of placenta growth factor (PIGF) and its specific receptor, flt-1, which are known to mediate angiogenesis, on the inflammatory process of rheumatoid arthritis (RA).Methods. Expression of PIGF and flt-1 in the synovial tissue of RA patients was examined using immunohistochemistry. Enzyme-linked immunosorbent assay was used to determine the concentrations of PIGF, tumor necrosis factor alpha (TNF alpha), and interleukin-6 (IL-6) in culture supernatants of either mononuclear cells or synoviocytes. The flt-1. expression level in mononuclear cells was analyzed by flow cytometry. Experimental arthritis was induced in mice either by immunization with type II collagen (CII) or by injection of anti-CII antibody.Results. PIGF was highly expressed in the synovium of RA patients, and its primary source was fibroblast-like synoviocytes (FLS). When stimulated with 1L-1 beta, FLS from RA patients produced higher amounts of PIGF than did FLS from patients with osteoarthritis. Exogenous PIGF specifically increased the production of TNF alpha and IL-6 in mononuclear cells from RA patients (but not those from healthy controls) via a calcineurin-dependent pathway. The response to PIGF was associated with increased expression of flt-1 on RA monocytes, which could be induced by IL-1 beta and TNFa. A novel anti-flt-1 hexapeptide, GNQWFI, abrogated the PIGF-induced increase in TNFa and IL-6 production, and also suppressed CII-induced arthritis and serum IL-6 concentrations in mice. Moreover, genetic ablation of PIGF prevented the development of anti-CII antibody-induced arthritis in mice.Conclusion. Our data suggest that enhanced expression of PIGF and flt-1 may contribute to rheumatoid inflammation by triggering production of proinflammatory cytokines. The use of the novel anti-flt-1 peptide, GNQWFI, may be an effective strategy for the treatment of RA.