Protease-activated receptor-1 down-regulates the murine inflammatory and humoral response to Helicobacter pylori.
Protease-activated receptor-1 down-regulates the murine inflammatory and humoral response to Helicobacter pylori.
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DOI：
10.1053/j.gastro.2009.08.043
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发表时间：
2010-02
期刊：
影响因子：
29.4
通讯作者：
J. Wee;Y. Chionh;Garrett Z Ng;Stacey N. Harbour;C. Allison;C. Pagel;E. Mackie;H. Mitchell;R. Ferrero;P. Sutton
中科院分区：
文献类型：
--
作者：
J. Wee;Y. Chionh;Garrett Z Ng;Stacey N. Harbour;C. Allison;C. Pagel;E. Mackie;H. Mitchell;R. Ferrero;P. Sutton
背景与目的幽门螺杆菌感染可导致多种病理改变，从无症状胃炎到腺癌。这些不同结局的原因是多因素的，包括调节螺杆菌诱导的胃炎严重程度的宿主因素。蛋白酶激活受体（PAR）是一种能够检测组织损伤和病原体的环境传感器。而PAR-2具有促炎活性，PAR-1可以保护胃粘膜免受化学损伤，以前都没有检查过它们在调节螺杆菌发病机制中的潜在作用。方法将PAR-1（-/-）、PAR-2（-/-）和野生型小鼠感染幽门螺杆菌2个月，然后用菌落形成试验、组织学和酶联免疫吸附试验检测幽门螺杆菌的定植水平、胃炎和血清抗体水平。原代上皮细胞对PAR-1激活的反应性通过钙动员测定来评估。原代上皮细胞，巨噬细胞，树突状细胞与幽门螺杆菌和核因子（NF）-κ B共培养，并通过酶联免疫吸附试验测定细胞因子分泌。结果感染后2个月，PAR-1（-/-）小鼠的H pylori水平显著降低，PAR-2（-/-）小鼠的H pylori水平显著升高。这种对定植的影响与炎症严重程度呈负相关。感染PAR-1（-/-）小鼠可诱导血清抗体应答增加。原代上皮细胞被PAR-1激活肽激活。幽门螺杆菌刺激PAR-1（-/-）小鼠的原代上皮细胞，而不是巨噬细胞或树突状细胞，诱导NF-κ B和促炎细胞因子巨噬细胞炎性蛋白（MIP）-2水平升高。PAR-1也下调MIP-2的分泌反应cag致病岛的活动。结论PAR-1对严重的幽门螺杆菌性胃炎具有保护作用。这可以通过抑制促炎细胞因子如MIP-2的产生来介导。
BACKGROUND & AIMS Helicobacter pylori infection results in a diversity of pathologies, from asymptomatic gastritis to adenocarcinoma. The reason for these diverse outcomes is multifactorial and includes host factors that regulate severity of Helicobacter-induced gastritis. Protease-activated receptors (PAR) are environmental sensors that can detect tissue damage and pathogens. Whereas PAR-2 has proinflammatory activity and PAR-1 can protect the gastric mucosa against chemical damage, neither has previously been examined for their potential roles in regulating Helicobacter pathogenesis. METHODS PAR-1(-/-), PAR-2(-/-), and wild-type mice were infected with H pylori for up to 2 months then colonization levels determined by colony-forming assay, gastritis by histology, and serum antibody levels by enzyme-linked immunosorbent assay. Responsiveness of primary epithelial cells to PAR-1 activation was assessed by calcium mobilization assay. Primary epithelial cells, macrophages, and dendritic cells were cocultured with H pylori and nuclear factor (NF)-kappaB, and cytokine secretion was determined by enzyme-linked immunosorbent assay. RESULTS Two months postinfection, H pylori levels were significantly reduced in PAR-1(-/-) and increased in PAR-2(-/-) mice. This effect on colonization was inversely correlated with inflammation severity. Infection of PAR-1(-/-) mice induced an increased serum antibody response. Primary epithelial cells were activated by a PAR-1-activating peptide. H pylori stimulation of primary epithelial cells, but not macrophages or dendritic cells, from PAR-1(-/-) mice induced increased levels of NF-kappaB and the proinflammatory cytokine macrophage-inflammatory protein (MIP)-2. PAR-1 also down-regulated MIP-2 secretion in response to cag pathogenicity island activity. CONCLUSIONS PAR-1 protects the host against severe Helicobacter-induced gastritis. This may be mediated by suppressing the production of proinflammatory cytokines such as MIP-2.