S100A12 通过晚期糖基化终产物受体和 p38 MAPK 信号通路抑制成纤维细胞迁移。
S100A12 inhibits fibroblast migration via the receptor for advanced glycation end products and p38 MAPK signaling.
机构信息
Department of Respirology (B2), Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo Ward, Chiba City, 260-8670, Japan.
出版信息
In Vitro Cell Dev Biol Anim. 2019 Sep;55(8):656-664. doi: 10.1007/s11626-019-00384-x. Epub 2019 Jul 11.
The migration of lung fibroblasts plays a pivotal role in wound repair and fibrotic processes in the lung. Although the receptor for advanced glycation end products (RAGE) has been implicated in the pathogenesis of lung diseases, its role in lung fibroblast migration is unclear. The current study examined the effect of three different RAGE ligands, namely, high mobility group box 1 (HMGB1), S100A12, and N-epsilon-(carboxymethyl) lysine (CML), on human fibronectin-directed human fetal lung fibroblast (HFL-1) migration. HMGB1 augmented, whereas S100A12 inhibited, HFL-1 migration in a concentration-dependent manner. CML did not affect HFL-1 migration. The effect of HMGB1 was not through RAGE. However, the effect of S100A12 was mediated by RAGE, but not Toll-like receptor 4. S100A12 did not exert a chemoattractant effect, but inhibited HFL-1 chemotaxis and/or chemokinesis. Moreover, S100A12 mediated HFL-1 migration through p38 mitogen-activated protein kinase (MAPK) but not through nuclear factor-kappa B, protein kinase A, phosphatase and tensin homolog deleted on chromosome 10, or cyclooxygenase. In addition, western blot analysis showed that S100A12 augmented p38 MAPK activity in the presence of human fibronectin. In conclusion, S100A12 inhibits lung fibroblast migration via RAGE-p38 MAPK signaling. This pathway could represent a therapeutic target for pulmonary conditions characterized by abnormal tissue repair and remodeling.
肺成纤维细胞的迁移在肺的伤口修复和纤维化过程中起着关键作用。尽管晚期糖基化终产物（RAGE）受体已被牵连到肺部疾病的发病机制中，但它在肺成纤维细胞迁移中的作用尚不清楚。本研究检测了三种不同的 RAGE 配体，即高迁移率族蛋白 B1（HMGB1）、S100A12 和 N-ε-（羧甲基）赖氨酸（CML），对人纤维连接蛋白指导的人胎肺成纤维细胞（HFL-1）迁移的影响。HMGB1 以浓度依赖的方式增强，而 S100A12 抑制 HFL-1 迁移。CML 不影响 HFL-1 迁移。HMGB1 的作用不是通过 RAGE 实现的。然而，S100A12 的作用是通过 RAGE 介导的，但不是通过 Toll 样受体 4 介导的。S100A12 没有发挥趋化作用，但抑制了 HFL-1 的趋化性和/或趋化运动。此外，S100A12 通过 p38 丝裂原活化蛋白激酶（MAPK）介导 HFL-1 迁移，但不通过核因子-κB、蛋白激酶 A、磷酸酶和张力蛋白同源物缺失 10 号染色体、环氧化酶。此外，Western blot 分析表明，在存在人纤维连接蛋白的情况下，S100A12 增强了 p38 MAPK 活性。总之，S100A12 通过 RAGE-p38 MAPK 信号通路抑制肺成纤维细胞迁移。该途径可能成为以异常组织修复和重塑为特征的肺部疾病的治疗靶点。
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