Porphyromonas gingivalis Gingipains Induce Cyclooxygenase-2 Expression and Prostaglandin E2 Production via ERK1/2-Activated AP-1 (c-Jun/c-Fos) and IKK/NF-κB p65 Cascades
Porphyromonas gingivalis Gingipains Induce Cyclooxygenase-2 Expression and Prostaglandin E2 Production via ERK1/2-Activated AP-1 (c-Jun/c-Fos) and IKK/NF-κB p65 Cascades
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DOI：
10.4049/jimmunol.2100866
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发表时间：
2022-03-01
影响因子：
4.4
通讯作者：
Ohara, Naoya
中科院分区：
文献类型：
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作者：
Nakayama, Masaaki;Naito, Mariko;Ohara, Naoya
牙龈卟啉单胞菌通常被认为是导致牙周炎的主要病原体之一，它的持续感染可能会增加患牙周炎的风险。促炎介质，包括IL-6、tnf - α和环氧化酶-2 (COX-2)IPGE(2)，与牙周炎的进展密切相关。在这项研究中，我们重点研究了牙龈卟啉菌产生的半胱氨酸蛋白酶“gingipains”、赖氨酸特异性gingipain、精氨酸特异性gingipain (Rgp) A和RgpB，并利用野生型菌株和几个基因缺失突变体（rgpA、RgpB、kgp和fimA）来阐明牙龈卟啉菌参与COX-2表达和PGE(2)的产生。我们用这些菌株感染人类单核细胞，即THP-1细胞和原代单核细胞，发现牙龈痛参与诱导COX-2表达和PGE(2)的产生。我们已经表明，蛋白酶活性的牙龈疼痛是至关重要的这些事件使用牙龈蛋白酶抑制剂。此外，生姜素诱导的COX-2表达/PGE(2)的产生需要ERK1/2和I kappa B激酶的激活，这些激酶分别激活了c-Jun/c-Fos （AP-1）和NF-kappa B p65两种转录因子。这些数据特别表明，生姜素通过ERK诱导的c-Fos表达对于c-Jun形成AP-1至关重要，AP-1和NF-kappa B p65的激活在COX-2表达/PGE(2)产生中起核心作用。因此，我们展示了（据我们所知）新的发现，牙龈蛋白酶活性的牙龈蛋白酶通过激活MEK/ERK/AP-1和I κ B激酶/ nf - κ B p65在人单核细胞中诱导COX-2表达和PGE(2)的产生。因此，牙痛很可能与牙周组织的炎症密切相关。
Porphyromonas gingivalis is commonly known as one of the major pathogens contributing to periodontitis, and its persistent infection may increase the risk for the disease. The proinflammatory mediators, including IL-6, TNF-alpha, and cyclooxygenase-2 (COX-2)IPGE(2), are closely associated with progression of periodontitis. In this study, we focused on the cysteine protease "gingipains," lysine-specific gingipain, arginine-specific gingipain (Rgp) A, and RgpB, produced by P. gingivalis, and used the wild-type strain and several gene-deletion mutants (rgpA, rgpB, kgp, and fimA) to elucidate the involvement of gingipains in COX-2 expression and PGE(2) production. We infected human monocytes, which are THP-1 cells and primary monocytes, with these bacterial strains and found that gingipains were involved in induction of COX-2 expression and PGE(2) production. We have shown that the protease activity of gingipains was crucial for these events by using gingipain inhibitors. Furthermore, activation of ERK1/2 and I kappa B kinase was required for gingipain-induced COX-2 expression/PGE(2) production, and these kinases activated two transcription factors, c-Jun/c-Fos (AP-1) and NF-kappa B p65, respectively. In particular, these data suggest that gingipain-induced c-Fos expression via ERK is essential for AP-1 formation with c-Jun, and activation of AP-1 and NF-kappa B p65 plays a central role in COX-2 expression/PGE(2) production. Thus, we show the (to our knowledge) novel finding that gingipains with the protease activity from P. gingivalis induce COX-2 expression and PGE(2) production via activation of MEK/ERK/AP-1 and I kappa B kinase/NF-kappa B p65 in human monocytes. Hence it is likely that gingipains closely contribute to the inflammation of periodontal tissues.