TLR4 Protein Contributes to Cigarette Smoke-induced Matrix Metalloproteinase-1 (MMP-1) Expression in Chronic Obstructive Pulmonary Disease
TLR4 Protein Contributes to Cigarette Smoke-induced Matrix Metalloproteinase-1 (MMP-1) Expression in Chronic Obstructive Pulmonary Disease
复制标题
DOI：
10.1074/jbc.m111.238824
复制
发表时间：
2011-08-26
影响因子：
4.8
通讯作者：
D'Armiento, Jeanine
中科院分区：
文献类型：
--
作者：
Geraghty, Patrick;Dabo, Abdoulaye J.;D'Armiento, Jeanine
香烟烟雾是与慢性阻塞性肺病发展相关的主要危险因素，并改变导致疾病病理的蛋白水解酶的表达。此前，我们报道过烟雾暴露会通过激活 ERK1/2 诱导基质金属蛋白酶-1 (MMP-1)，这对于肺气肿的发展至关重要。迄今为止，香烟烟雾诱导 MMP-1 表达的上游信号通路尚不清楚。这项研究表明，香烟烟雾通过激活 TLR4 信号级联来介导 MMP-1 表达。体外细胞培养研究表明，香烟烟雾诱导的 MMP-1 受 TLR4 通过 MyD88/IRAK1 调节。阻断 TLR4 或抑制 IRAK1 可防止香烟烟雾诱导 MMP-1。暴露于高水平香烟烟雾的小鼠表现出 TLR4 表达增加。为了进一步证实该信号通路的体内相关性，发现暴露于急性香烟烟雾的兔子的 TLR4 信号传导和随后的 MMP-1 表达升高。此外，吸烟者的肺部 TLR4 和 MMP-1 水平升高。因此，我们的数据表明，TLR4 信号通过 MyD88 和 IRAK1 在香烟烟雾诱导 MMP-1 中起主要作用。 TLR4 通路作为烟雾诱导的蛋白酶产生调节剂的鉴定为慢性阻塞性肺病的未来治疗提供了一系列新靶标。
Cigarette smoke is the major risk factor associated with the development of chronic obstructive pulmonary disease and alters expression of proteolytic enzymes that contribute to disease pathology. Previously, we reported that smoke exposure leads to the induction of matrix metalloproteinase-1 (MMP-1) through the activation of ERK1/2, which is critical to the development of emphysema. To date, the upstream signaling pathway by which cigarette smoke induces MMP-1 expression has been undefined. This study demonstrates that cigarette smoke mediates MMP-1 expression via activation of the TLR4 signaling cascade. In vitro cell culture studies demonstrated that cigarette smoke-induced MMP-1 was regulated by TLR4 via MyD88/IRAK1. Blockade of TLR4 or inhibition of IRAK1 prevented cigarette smoke induction of MMP-1. Mice exposed to acute levels of cigarette smoke exhibited increased TLR4 expression. To further confirm the in vivo relevance of this signaling pathway, rabbits exposed to acute cigarette smoke were found to have elevated TLR4 signaling and subsequent MMP-1 expression. Additionally, lungs from smokers exhibited elevated TLR4 and MMP-1 levels. Therefore, our data indicate that TLR4 signaling, through MyD88 and IRAK1, plays a predominant role in MMP-1 induction by cigarette smoke. The identification of the TLR4 pathway as a regulator of smoke-induced protease production presents a series of novel targets for future therapy in chronic obstructive pulmonary disease.