Resistin is an adipokine with potent proinflammatory properties, acting as a potential regulator of inflammation. Several studies proposed resistin to be an important link between obesity and insulin resistance. The obesity-related inflammatory state is linked to the increased risk of developing cardiovascular diseases and type 2 diabetes mellitus. The aim of this study is to determine whether resistin, a cytokine with an important role in the inflammatory process associated with atherosclerosis, induces the expression of fractalkine (CX3CL1) and CX3CR1 in human smooth muscle cells (SMC) and to investigate the potential signaling pathways involved.

Cultured human aortic SMC were stimulated with 100ng/ml resistin for 4, 6, 12, and 24h and then the CX3CL1 and CX3CR1 expression was assessed by quantitative RT-PCR and Western-blot. We found that resistin up-regulated CX3CL1 and CX3CR1 in SMC and induced the phosphorylation of p38MAPK and STAT3. Inhibitors of p38MAPK, JAK-STAT and NF-kB and AP-1reduced significantly the CX3CL1 and CX3CR1 expression. Knockdown of STAT1 and STAT3 with decoy oligodeoxinucleotides and silencing p65 and cjun with siRNA down-regulated the CX3CL1 and CX3CR1 expression. Anti-TLR4 antibody and pertussis toxin reduced CX3CL1 and CX3CR1 protein expression. The xCELLigence experiments revealed that resistin may use Gi-proteins for its effect on SMC. The resistin-induced CX3CL1 had chemotactic effect on monocytes transmigration.

Resistin contributes to the pro-inflammatory state of SMC by up-regulation of CX3CL1 and CX3CR1 expression via a mechanism involving NF-kB, AP-1 and STAT1/3 transcription factors. Resistin employs TLR 4 and Gi proteins signalling for its effect on SMC. Resistin-induce CX3CL1 is functional in monocytes chemotaxis. The data reveal new mechanisms by which resistin contributes to the development of atherosclerosis and indicate this cytokine as a novel therapeutic target.