Park Jun Won, Lee Su Hyung, Go Du Min, Kim Hark Kyun, Kwon Hyo-Jung, Kim Dae-Yong
1] Department of Veterinary Pathology, College of Veterinary Medicine, Seoul National University, Seoul, Korea [2] National Cancer Center, Goyang, Gyeonggi, Korea.
Department of Veterinary Pathology, College of Veterinary Medicine, Seoul National University, Seoul, Korea.
Lab Invest. 2015 Jun;95(6):660-71. doi: 10.1038/labinvest.2015.47. Epub 2015 Apr 13.
Osteopontin (OPN) is a multifunctional protein that plays a role in many physiological and pathological processes, including inflammation and tumorigenesis. Here, we investigated the involvement of OPN in Helicobacter pylori (HP)-induced gastritis using OPN knockout (KO) mice and OPN knockdown (KD) cell lines. HP-infected OPN KO mice showed significantly reduced gastritis compared with wild-type (WT) mice with decreased infiltration of macrophages and a reduction in HP-induced upregulation of IL-1β, TNF-α, and IFN-γ. HP-exposed OPN KD gastric cancer cells and macrophage-like cells showed an attenuated induction of these cytokines. We also demonstrated a reduction in the migration of monocytic and macrophage-like cells toward conditioned media harvested from HP-exposed OPN KD gastric cancer cells as well as reduced migration ability of OPN KD cells itself. In addition, HP-infected OPN KO mice showed decreased epithelial cell proliferation compared with HP-infected WT mice, in association with a reduction in MAPK pathway activation. OPN KD gastric cancer cell lines also showed lower proliferative activity and reduced MAPK activation than shRNA control cells after HP co-culture or after IL-1β and TNF-α treatment. Taken together, these results indicate that OPN exerts a considerable influence on HP-induced gastritis by modulating the production of cytokines and contributing to macrophage infiltration. Moreover, OPN-mediated activation of the MAPK pathway in gastric epithelial cells might contribute to epithelial changes following HP infection.
骨桥蛋白（OPN）是一种多功能蛋白质，在许多生理和病理过程中发挥作用，包括炎症和肿瘤发生。在此，我们使用OPN基因敲除（KO）小鼠和OPN基因敲低（KD）细胞系研究了OPN在幽门螺杆菌（HP）诱导的胃炎中的作用。与野生型（WT）小鼠相比，HP感染的OPN KO小鼠的胃炎明显减轻，巨噬细胞浸润减少，HP诱导的IL-1β、TNF-α和IFN-γ上调也减少。暴露于HP的OPN KD胃癌细胞和巨噬细胞样细胞中这些细胞因子的诱导减弱。我们还证明，单核细胞和巨噬细胞样细胞向从暴露于HP的OPN KD胃癌细胞收获的条件培养基的迁移减少，以及OPN KD细胞本身的迁移能力降低。此外，与HP感染的WT小鼠相比，HP感染的OPN KO小鼠的上皮细胞增殖减少，这与MAPK途径激活的减少有关。在HP共培养或IL-1β和TNF-α处理后，OPN KD胃癌细胞系也显示出比shRNA对照细胞更低的增殖活性和MAPK激活减少。综上所述，这些结果表明，OPN通过调节细胞因子的产生和促进巨噬细胞浸润，对HP诱导的胃炎产生相当大的影响。此外，OPN介导的胃上皮细胞中MAPK途径的激活可能有助于HP感染后的上皮变化。
