Neutrophil serine proteinases activate human nonepithelial cells to produce inflammatory cytokines through protease-activated receptor 2 (Retracted Article)
Neutrophil serine proteinases activate human nonepithelial cells to produce inflammatory cytokines through protease-activated receptor 2 (Retracted Article)
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DOI：
10.4049/jimmunol.170.11.5690
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发表时间：
2003-06-01
影响因子：
4.4
通讯作者：
Sugawara, S
中科院分区：
文献类型：
--
作者：
Uehara, A;Muramoto, K;Sugawara, S
蛋白酶激活受体（PARs）是一组G蛋白偶联受体，通过暴露其拴链配体进行蛋白水解而激活。最近，我们报道了一种中性粒细胞衍生的丝氨酸蛋白酶蛋白酶3 （PR3）通过PAR-2激活人口腔上皮细胞。本研究检测了其他中性粒细胞丝氨酸蛋白酶、人白细胞弹性酶（HLE）和组织蛋白酶G （Cat G）是否能激活非上皮细胞、人牙龈成纤维细胞（HGF）。HLE和Cat G以及PR3激活HGF产生IL-8和单核细胞趋化蛋白1。人口腔上皮细胞不表达HGF，而表达分泌性白细胞蛋白酶抑制剂（HLE和Cat G的抑制剂）的mRNA和蛋白，重组分泌性白细胞蛋白酶抑制剂明显抑制HLE和Cat G诱导的HGF活化，而不抑制PR3诱导的HGF活化。HGF在细胞内和细胞表面表达PAR-1和PAR-2 mRNA。HLE和Cat G通过暴露PAR-2的拴链配体来切割PAR-2 N端对应的肽。胰蛋白酶是PAR-2的激动剂，合成的PAR-2激动剂肽诱导细胞内Ca2+动员，并使细胞对HLE和Cat g的后续刺激产生抗性。HLE和Cat Q诱导的细胞因子和PAR-2激动剂肽的产生被磷脂酶c的抑制完全消除。这些发现表明中性粒细胞丝氨酸蛋白酶具有通过PAR-2激活人非上皮细胞产生炎症细胞因子的同等能力，并可能控制许多炎症牙周炎等疾病。
Protease-activated receptors (PARs) compose a family of G protein-coupled receptors activated by proteolysis with exposure of their tethered ligand. Recently, we reported that a neutrophil-derived serine proteinase, proteinase 3 (PR3), activated human oral epithelial cells through PAR-2. The present study examined whether other neutrophil serine proteinases, human leukocyte elastase (HLE), and cathepsin G (Cat G) activate nonepithelial cells, human gingival fibroblasts (HGF). HLE and Cat G as well as PR3 activated HGF to produce IL-8 and monocyte chemoattractant protein 1. Human oral epithelial cells but not HGF express mRNA and protein of secretory leukocyte protease inhibitor, an inhibitor of HLE and Cat G, and recombinant secretory leukocyte protease inhibitor clearly inhibited the activation of HGF induced by HLE and Cat G but not by PR3. HGF express PAR-1 and PAR-2 mRNA in the cells and the proteins on the cell surface. HLE and Cat G cleaved the peptide corresponding to the N terminus of PAR-2 with exposure of its tethered ligand. Treatment with trypsin, an agonist for PAR-2, and a synthetic PAR-2 agonist peptide induced intracellular Ca2+ mobilization and rendered cells refractory to subsequent stimulation with HLE and Cat G. The production of cytokine induced by HLE and Cat Q and the PAR-2 agonist peptide was completely abolished by inhibition of phospholipase C. These findings suggest that neutrophil serine proteinases have equal ability to activate human nonepithelial cells through PAR-2 to produce inflammatory cytokines and may control a number of inflammatory processes such as periodontitis.