title: Subendothelial resistin enhances monocyte transmigration in a co-culture of human endothelial and smooth muscle cells by mechanisms involving fractalkine, MCP-1 and activation of TLR4 and Gi/o proteins signaling.
abstract: 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.
authors: Institute of Cellular Biology and Pathology "Nicolae Simionescu", Bucharest 050568, Romania. Electronic address: monica.pirvulescu@icbp.ro.
authors: Monica Madalina
authors: MM
authors: Pirvulescu
authors: Institute of Cellular Biology and Pathology "Nicolae Simionescu", Bucharest 050568, Romania.
authors: Ana Maria
authors: AM
authors: Gan
authors: Institute of Cellular Biology and Pathology "Nicolae Simionescu", Bucharest 050568, Romania.
authors: Daniela
authors: D
authors: Stan
authors: Institute of Cellular Biology and Pathology "Nicolae Simionescu", Bucharest 050568, Romania.
authors: Viorel
authors: V
authors: Simion
authors: Institute of Cellular Biology and Pathology "Nicolae Simionescu", Bucharest 050568, Romania.
authors: Manuela
authors: M
authors: Calin
authors: Institute of Cellular Biology and Pathology "Nicolae Simionescu", Bucharest 050568, Romania.
authors: Elena
authors: E
authors: Butoi
authors: Institute of Cellular Biology and Pathology "Nicolae Simionescu", Bucharest 050568, Romania.
authors: Ileana
authors: I
authors: Manduteanu
mesh_terms: D018932:Chemokine CCL2 / Q000378:metabolism*; D054428:Chemokine CX3CL1 / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D006801:Humans; D009000:Monocytes / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D052243:Resistin / Q000378:metabolism*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D054428:Chemokine CX3CL1; D052243:Resistin; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D019206:GTP-Binding Protein alpha Subunits, Gi-Go
keywords: Fractalkine; MCP-1; Subendothelial resistin; TLR4; Vascular inflammation