Department of Biochemistry, Faculty of Medicine, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand.
J Innate Immun. 2013;5(1):72-83. doi: 10.1159/000342928. Epub 2012 Oct 23.
Periodontal disease is caused by microorganisms and host-derived inflammation involving increased cyclooxygenase-2 (COX-2) expression and prostaglandin E(2) (PGE(2)) production. We previously demonstrated that human β-defensin-3 induces COX-2 and PGE(2) in human gingival fibroblasts (HGFs). We, therefore, aimed to examine the inducible effects of LL-37, the only cathelicidin expressed in humans, on COX-2 expression and PGE(2) synthesis in HGFs and to elucidate the relevant signaling pathways. The COX-2 expression was upregulated by LL-37 in dose- and time-dependent manners. Accordingly, the synthesis of PGE(2) in cell-free culture supernatants was raised by LL-37 (p < 0.01) and blocked by NS-398, a specific COX-2 inhibitor (p < 0.01). P2X inhibitors and a neutralizing antibody against P2X(7) purinergic receptor significantly abrogated COX-2 induction and PGE(2) production by LL-37 (p < 0.01). LL-37 upregulated COX-2 expression and PGE(2) synthesis via activation of extracellular signal-regulated kinase (ERK) and p46 c-Jun N-terminal kinase (JNK), while interleukin-1β did so via nuclear factor-ĸB and all three mitogen-activated protein kinases. In summary, LL-37 can control arachidonic acid metabolism by induction of COX-2 expression and PGE(2) synthesis via the P2X(7) receptor, ERK, and p46 JNK. The pro-inflammatory effects of LL-37 may be essential for initiating oral mucosal inflammation in periodontal disease.
牙周病是由微生物和宿主炎症引起的，涉及环氧化酶-2（COX-2）表达增加和前列腺素 E2（PGE2）产生。我们之前证明，人β-防御素-3 诱导人牙龈成纤维细胞（HGFs）中 COX-2 和 PGE2 的表达。因此，我们旨在研究人类唯一表达的 cathelicidin LL-37 对 HGFs 中 COX-2 表达和 PGE2 合成的诱导作用，并阐明相关信号通路。COX-2 的表达被 LL-37 以剂量和时间依赖的方式上调。相应地，LL-37 提高了细胞游离培养上清液中 PGE2 的合成（p<0.01），并被 COX-2 特异性抑制剂 NS-398 阻断（p<0.01）。P2X 抑制剂和针对 P2X7 嘌呤能受体的中和抗体显著阻断了 LL-37 诱导的 COX-2 表达和 PGE2 产生（p<0.01）。LL-37 通过激活细胞外信号调节激酶（ERK）和 p46 c-Jun N-末端激酶（JNK）上调 COX-2 表达和 PGE2 合成，而白细胞介素-1β 通过核因子-κB 和三种丝裂原激活蛋白激酶来实现这一点。总之，LL-37 通过 P2X7 受体、ERK 和 p46 JNK 诱导 COX-2 表达和 PGE2 合成，从而控制花生四烯酸代谢。LL-37 的促炎作用对于启动牙周病中的口腔黏膜炎症可能是必要的。
