Role of c-Jun N-terminal protein kinase 1/2 (JNK1/2) in macrophage-mediated MMP-9 production in response to Moraxella catarrhalis lipooligosaccharide (LOS).
Role of c-Jun N-terminal protein kinase 1/2 (JNK1/2) in macrophage-mediated MMP-9 production in response to Moraxella catarrhalis lipooligosaccharide (LOS).
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DOI：
10.1371/journal.pone.0037912
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Gu XX
中科院分区：
文献类型：
--
作者：
Hassan F;Ren D;Zhang W;Gu XX
卡他莫拉菌是一种革兰氏阴性菌，是儿童中耳炎（OM）的主要病原体。最近的报告提供了强有力的证据，存在高水平的基质金属蛋白酶（MMPs）的渗出液中患有OM的儿童，然而，MMPs产生的确切机制目前尚不清楚。我们假设MMPs在M.卡他性脂寡糖（LOS）。在这份报告中，我们证明，在体外刺激小鼠巨噬细胞RAW 264.7细胞LOS导致MMP-9的分泌，通过ELISA和酶谱测定。我们还表明，ERK 1/2和p38激酶的抑制完全阻断LOS诱导的MMP-9的产生。相比之下，特异性抑制剂SP 600125抑制JNK 1/2实际上分别在mRNA和蛋白质水平上增加MMP-9的表达和产生水平几乎5倍。通过使用siRNA敲低JNK 1/2证实了后一结果。在体外小鼠骨髓源性巨噬细胞中观察到类似的结果。与LOS诱导的MMP-9水平增加的SP 600125的存在下，我们发现了相应的剂量依赖性抑制TIMP-1（基质金属蛋白酶组织抑制剂-1）的分泌。随后的体外研究的结果提供了证据表明，当JNK 1/2在用LOS刺激之前被抑制时，与对照细胞或单独用LOS处理的细胞相比，它显著增加了巨噬细胞迁移和侵袭的程度。这些研究的结果有助于加深对儿童OM伴积液的潜在病理生理学的理解。
Moraxella catarrhalis is a Gram negative bacterium and a leading causative agent of otitis media (OM) in children. Recent reports have provided strong evidence for the presence of high levels of matrix metalloproteinase (MMPs) in effusion fluids from children suffering with OM, however, the precise mechanisms by which MMPs are generated are currently unknown. We hypothesized that MMPs are secreted from macrophages in the presence of M. catarrhalis lipooligosaccharide (LOS). In this report, we demonstrate that in vitro stimulation of murine macrophage RAW 264.7 cells with LOS leads to secretion of MMP-9 as determined by ELISA and zymogram assays. We have also shown that inhibition of ERK1/2 and p38 kinase completely blocked LOS induced MMP-9 production. In contrast, inhibition of JNK1/2 by the specific inhibitor SP600125 actually increased the level of expression and production of MMP-9 at both mRNA and protein levels, respectively by almost five fold. This latter result was confirmed by knocking down JNK1/2 using siRNA. Similar results have been observed in murine bone marrow derived macrophages in vitro. In contrast to and in parallel with the LOS-induced increased levels of MMP-9 in the presence of SP600125, we found a corresponding dose-dependent inhibition of TIMP-1 (tissue inhibitor of matrix metalloproteinase-1) secretion. Results of subsequent in vitro studies provided evidence that when JNK1/2 was inhibited prior to stimulation with LOS, it significantly increased both the extent of macrophage cell migration and invasion compared to control cells or cells treated with LOS alone. The results of these studies contribute to an increased understanding of the underlying pathophysiology of OM with effusion in children.
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