Palmitate induces interleukin-8 expression in human aortic vascular smooth muscle cells via Toll-like receptor 4/nuclear factor-κB pathway (TLR4/NF-κB-8)

Jinxing Quan, Jing Liu, Xiaobo Gao, Juxiang Liu, Haijing Yang, Wei Chen, Weihua Li, Yonghong Li, Weiguo Yang, Baoli Wang
Journal of Diabetes 2014, 6 (1): 33-41

BACKGROUND: Recent evidence demonstrates that saturated free fatty acids (FFAs) induce the inflammatory response via the Toll-like receptor 4 (TLR4) pathway. Interleukin-8 (IL-8) is a proinflammatory cytokine that induces vascular smooth muscle cell proliferation and migration in vitro. However, the regulation of IL-8 expression by palmitate in human vascular smooth muscle cells (HVSMCs) has not been clarified. The aim of this study was to investigate the regulation of IL-8 expression by free fatty acids and determine the underlying mechanisms in HVSMCs.

METHODS: Human vascular smooth muscle cells were cultured and treated with palmitate, various signaling inhibitors or TLR4 shRNA adenovirus, and the mRNA and protein expression levels of IL-8, nuclear factor κB (NF-κB) luciferase activity and NF-κB p65 binding activity were studied.

RESULTS: Palmitate induced IL-8 mRNA expression and secretion in a dose-dependent manner. Palmitate significantly stimulated both nuclear factor κB (NF-κB) luciferase activity and NF-κB p65 binding activity, which were markedly diminished by pretreatment with the NF-κB inhibitor, parthenolide. Parthenolide pretreatment also abolished IL-8 mRNA and protein induction by palmitate. By contrast, disrupting the ceramide and phosphoinositide-3 kinase (PI3K) pathways with myriocin and wortmannin did not affect palmitate-induced IL-8 expression. Inhibition of protein kinase C (PKC) activation with calphostin C and chelerythrine partially suppressed palmitate-stimulated IL-8 expression, but it had no effect on palmitate-induced NF-κB activation. Finally, knockdown of TLR4 markedly abolished palmitate-induced NF-κB activation and IL-8 expression.

CONCLUSIONS: Palmitate induces IL-8 gene expression in HVSMCs through the TLR4/NF-κB pathway.

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