TRPV4调解IL-1-诱导的Ca2+信号传递,ERK激活和MMP表达
Qin Wang1, Chenfan Ji1, Aiman Ali1
1Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada.
概括
瞬态受体潜在化物4 (TRPV4) 通道介导纤维细胞中的 (Ca2+) 流入,这对炎症反应至关重要. 抑制TRPV4可能为炎症性疾病中的矩阵降解提供了一个新的治疗策略.
科学领域:
- 细胞生物学 细胞生物学
- 免疫学 免疫学 免疫学
- 药理学 药理学是指药理学的学科.
背景情况:
- 纤维细胞中介质素-1β (IL-1β) 信号激活细胞外调节激酶 (ERK) 和矩阵金属蛋白酶-1 (MMP1) 表达.
- 这些IL-1β诱导的过程需要 (Ca2+) 流,但IL-1受体 (IL-1R1) 产生的Ca2+信号的机制尚不清楚.
- 瞬态受体潜在化物4 (TRPV4) 通道通过Ca2+透参与了病理矩阵降解.
研究的目的:
- 调查TRPV4是否调解IL-1β刺激的牙纤维细胞中ERK信号传递所必需的Ca2+流.
- 阐明TRPV4在IL-1R1诱导的Ca2+信号传递和随后的矩阵重塑中的作用.
主要方法:
- 在人类和小鼠的牙纤维细胞中对TRPV4的免疫抑制.
- 用IL-1β,TRPV4激动剂 (GSK101) 和IL-1受体对抗剂刺激纤维细胞.
- 细胞内Ca2+ ([Ca2+]i) 水平,MMP1和MMP13表达的评估.
- 使用TRPV4淘汰和孔突变细胞,以及TRPV4抑制剂 (RN1734).
- 通过共免疫沉和质谱学研究蛋白质-蛋白质相互作用,包括Src酶活性.
主要成果:
- 刺激IL-1β会增加人类纤维细胞中的MMP1表达,但不会增加TRPV4表达.
- 在小鼠纤维细胞中,IL-1β显著增加了细胞内Ca2+ ([Ca2+]i) 和MMP13的表达,这取决于TRPV4.
- TRPV4淘汰,孔子突变或抑制阻断了IL-1β诱导的Ca2+过渡体和MMP13表达.
- TRPV4的激活模仿了IL-1β对Ca2+和ERK信号传递的影响,而这些信号在TRPV4缺乏细胞中是不存在的.
- 与Src相关的蛋白质相关的TRPV4,以及Src抑制降低了IL-1β诱导的Ca2+反应.
结论:
- TRPV4调解IL-1β诱导的Ca2+流入和随后纤维细胞中的矩阵重塑.
- 在IL-1R1的下游,TRPV4的功能可能是通过与Src家族激酶的关联.
- 向TRPV4提供了一种潜在的治疗策略,以抑制炎症条件下的矩阵降解.
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