Pirvulescu Monica Madalina, Gan Ana Maria, Stan Daniela, Simion Viorel, Calin Manuela, Butoi Elena, Manduteanu Ileana
Institute of Cellular Biology and Pathology "Nicolae Simionescu", Bucharest 050568, Romania.
Institute of Cellular Biology and Pathology "Nicolae Simionescu", Bucharest 050568, Romania.
Int J Biochem Cell Biol. 2014 May;50:29-37. doi: 10.1016/j.biocel.2014.01.022. Epub 2014 Feb 6.
The cytokine resistin and the chemokine fractalkine (FKN) were found at increased levels in human atherosclerotic plaque, in the subendothelium, but their role in this location still needs to be characterized. Recently, high local resistin in the arterial vessel wall was shown to contribute to an enhanced accumulation of macrophages by mechanisms that need to be clarified. Our recent data showed that resistin activated smooth muscle cells (SMC) by up-regulating FKN and MCP-1 expression and monocyte chemotaxis by activating toll-like receptor 4 (TLR4) and Gi/o proteins. Since in the vessel wall both endothelial cells (EC) and SMC respond to cytokines and promote atherosclerosis, we questioned whether subendothelial resistin (sR) has a role in vascular cells cross-talk leading to enhanced monocyte transmigration and we investigated the mechanisms involved. To this purpose we used an in vitro system of co-cultured SMC and EC activated by sR and we analyzed monocyte transmigration. Our results indicated that: (1) sR enhanced monocyte transmigration in EC/SMC system compared to EC cultured alone; (2) sR activated TLR4 and Gi/o signaling in EC/SMC system and induced the secretion of more FKN and MCP-1 compared to EC cultured alone and used both chemokines to specifically recruit monocytes by CX3CR1 and CCR2 receptors. Moreover, FKN produced by resistin in EC/SMC system, by acting on CX3CR1 on EC/SMC specifically contributes to MCP-1 secretion in the system and to the enhanced monocyte transmigration. Our study indicates new possible targets for therapy to reduce resistin-dependent enhanced macrophage infiltration in the atherosclerotic arterial wall.
细胞因子抵抗素和趋化因子 fractalkine（FKN）在人类动脉粥样硬化斑块的内皮下层中水平升高，但它们在该部位的作用仍有待明确。最近，动脉血管壁中局部抵抗素水平升高被证明通过尚待阐明的机制促进巨噬细胞的积聚增加。我们最近的数据表明，抵抗素通过上调 FKN 和 MCP-1 的表达激活平滑肌细胞（SMC），并通过激活 Toll 样受体 4（TLR4）和 Gi/o 蛋白促进单核细胞趋化。由于在血管壁中内皮细胞（EC）和平滑肌细胞均对细胞因子作出反应并促进动脉粥样硬化，我们质疑内皮下抵抗素（sR）在导致单核细胞迁移增强的血管细胞相互作用中是否发挥作用，并研究了其中涉及的机制。为此，我们使用了由 sR 激活的 SMC 和 EC 共培养的体外系统，并分析了单核细胞迁移情况。我们的结果表明：（1）与单独培养的 EC 相比，sR 在 EC/SMC 系统中增强了单核细胞迁移；（2）与单独培养的 EC 相比，sR 在 EC/SMC 系统中激活了 TLR4 和 Gi/o 信号传导，并诱导分泌更多的 FKN 和 MCP-1，且利用这两种趋化因子通过 CX3CR1 和 CCR2 受体特异性募集单核细胞。此外，抵抗素在 EC/SMC 系统中产生的 FKN 通过作用于 EC/SMC 上的 CX3CR1 特异性促进了系统中 MCP-1 的分泌以及单核细胞迁移的增强。我们的研究表明了新的可能治疗靶点，以减少动脉粥样硬化动脉壁中依赖抵抗素的巨噬细胞浸润增强。
