Muc1 Cell Surface Mucin Attenuates Epithelial Inflammation in Response to a Common Mucosal Pathogen
Muc1 Cell Surface Mucin Attenuates Epithelial Inflammation in Response to a Common Mucosal Pathogen
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DOI：
10.1074/jbc.m110.121319
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发表时间：
2010-07-02
影响因子：
4.8
通讯作者：
Lillehoj, Erik P.
中科院分区：
文献类型：
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作者：
Guang, Wei;Ding, Hua;Lillehoj, Erik P.
幽门螺杆菌感染的胃粘膜引起一种积极的慢性炎症，这是密切相关的发展，十二指肠和胃溃疡和胃癌。然而，超过80%的H.除了组织学炎症外，幽门螺杆菌是无症状的，并且还不知道什么因素影响细菌相关性胃炎和相关疾病的发病率和特征。由于以前的研究表明，Muc 1上皮糖蛋白抑制急性肺部感染的铜绿假单胞菌的炎症，我们问Muc 1是否也可能反调节胃炎症反应的H。幽门感染实验性H后，与Muc 1（+/+）小鼠相比，Muc 1（-/-）小鼠胃内细菌定植增加，TNF-α和角质形成细胞趋化因子转录水平更高。幽门感染与表达Muc 1的细胞相比，通过RNA干扰敲低AGS人胃上皮细胞中Muc 1表达与I κ B α磷酸化增加、NF-κ B活化和核转位增强以及白细胞介素-8产生增强相关。相反，与内源性表达Muc 1的细胞相比，Muc 1过表达与NF-κ B活化减少、白细胞介素-8产生减少和I κ B激酶β（IKK β）/IKK γ共免疫沉淀减少相关。用Muc 1加IKK β共转染AGS细胞，而不是无催化活性的IKK β突变体，逆转了Muc 1的抑制作用。最后，Mu 1与IKK γ形成免疫共沉淀复合物，但不与IKK β形成免疫共沉淀复合物。这些结果与Muc 1与IKK γ结合，从而抑制催化活性IKK复合物的形成并阻断H. pylori刺激I κ B α磷酸化、NF-κ B活化和下游炎症反应。
Helicobacter pylori infection of the gastric mucosa causes an active-chronic inflammation that is strongly linked to the development of duodenal and gastric ulcers and stomach cancer. However, greater than 80% of individuals infected with H. pylori are asymptomatic beyond histologic inflammation, and it is unknown what factors influence the incidence and character of bacterial-associated gastritis and related disorders. Because previous studies demonstrated that the Muc1 epithelial glycoprotein inhibited inflammation during acute lung infection by Pseudomonas aeruginosa, we asked whether Muc1 might also counter-regulate gastric inflammation in response to H. pylori infection. Muc1(-/-) mice displayed increased bacterial colonization of the stomach and greater TNF-alpha and keratinocyte chemoattractant transcript levels compared with Muc1(+/+) mice after experimental H. pylori infection. Knockdown of Muc1 expression in AGS human gastric epithelial cells by RNA interference was associated with increased phosphorylation of I kappa B alpha, augmented activation and nuclear translocation of NF-kappa B, and enhanced production of interleulin-8 compared with Muc1-expressing cells. Conversely, Muc1 overexpression was correlated with decreased NF-kappa B activation, reduced interleulin-8 production, and diminished I kappa B kinase beta (IKK beta)/IKK gamma coimmunoprecipitation compared with cells expressing Muc1 endogenously. Cotransfection of AGS cells with Muc1 plus IKK beta, but not a catalytically inactive IKK beta mutant, reversed the Muc1 inhibitory effect. Finally, Muc1 formed a coimmunoprecipitation complex with IKK gamma but not with IKK beta. These results are consistent with the hypothesis that Muc1 binds to IKK gamma, thereby inhibiting formation of the catalytically active IKK complex and blocking the ability of H. pylori to stimulate I kappa B alpha phosphorylation, NF-kappa B activation, and downstream inflammatory responses.