The action of the mast cell product tryptase on cyclooxygenase-2 (COX2) and subsequent fibroblast proliferation involves activation of the extracellular signal-regulated kinase isoforms 1 and 2 (erk1/2)
The action of the mast cell product tryptase on cyclooxygenase-2 (COX2) and subsequent fibroblast proliferation involves activation of the extracellular signal-regulated kinase isoforms 1 and 2 (erk1/2)
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DOI：
10.1016/j.cellsig.2004.09.017
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发表时间：
2005-04-01
影响因子：
4.8
通讯作者：
Mayerhofer, A
中科院分区：
文献类型：
--
作者：
Frungieri, MB;Albrecht, M;Mayerhofer, A
肥大细胞产物类胰蛋白酶通过蛋白酶激活受体2（PAR 2）诱导环氧合酶-2（COX 2）和15-脱氧前列腺素J2（15 d-PGJ 2）合成。15 d-PGJ 2通过核过氧化物酶体促增殖剂激活受体γ（PPARgamma），随后引起成纤维细胞增殖。在人成纤维细胞（HFFF 2）中，cDNA阵列、RT-PCR和Western blotting研究表明类胰蛋白酶上调c-jun、c-fos和COX 2的表达，并磷酸化细胞外信号调节激酶亚型1和2（erk 1/2），而非15 d-PGJ 2。此外，类胰蛋白酶对erk 1/2，c-jun，c-fos，COX 2和细胞增殖的影响被有丝分裂原活化蛋白激酶激酶（MEK）抑制剂PD 98059阻止。其他激酶[P38，应激活化蛋白激酶/c-jun N-末端激酶（SAPK/JUNK），erk 5]，细胞内Ca 2+或cAMP不受类胰蛋白酶/PAR 2的影响。我们的研究确定了导致诱导COX 2和成纤维细胞增殖的关键细胞内事件，即纤维化的基石。(C)2004年爱思唯尔公司All rights reserved.
The mast cell product tryptase, via protease-activated receptor 2 (PAR2), induces cyclooxygenase-2 (COX2) and 15-deoxy-prostaglandin J2 (15d-PGJ2) synthesis. 15d-PGJ2, through the nuclear peroxisome proliterator activated receptor gamma (PPARgamma), subsequently causes fibroblast proliferation. In this study we attempted to determine initial events of the tryptase/PAR2 signaling pathway leading to COX2 induction and fibroblast proliferation.In human fibroblasts (HFFF2), cDNA array, RT-PCR and Western blotting studies demonstrated that tryptase, but not 15d-PGJ2, up-regulates c-jun, c-fos and COX2 expression, and phosphorylates the extracellular signal-regulated kinase isoforms 1 and 2 (erk1/2). Furthermore, tryptase effects on erk1/2, c-jun, c-fos, COX2 and cell proliferation were prevented by PD98059, an inhibitor of the mitogen-activated protein kinase kinase (MEK). Other kinases [P38, stress-activated protein kinase/c-jun N-terminal kinase (SAPK/JUNK), erk5], intracellular Ca2+ or cAMP were not affected by tryptase/PAR2. Our study identifies crucial intracellular events leading to induction of COX2 and fibroblast proliferation, i.e. a cornerstone of fibrosis. (C) 2004 Elsevier Inc. All rights reserved.