Acid sphingomyelinase plays a key role in palmitic acid-amplified inflammatory signaling triggered by lipopolysaccharide at low concentrations in macrophages
Acid sphingomyelinase plays a key role in palmitic acid-amplified inflammatory signaling triggered by lipopolysaccharide at low concentrations in macrophages
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DOI：
10.1152/ajpendo.00251.2013
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发表时间：
2013-10-01
影响因子：
5.1
通讯作者：
Huang, Yan
中科院分区：
文献类型：
--
作者：
Jin, Junfei;Zhang, Xiaoming;Huang, Yan
牙周病在糖尿病患者中比在非糖尿病患者中更为普遍和严重。除了糖尿病，大量的研究已经证明了肥胖和慢性牙周病之间的联系。然而，其潜在机制尚未得到很好的理解。由于肥胖患者血浆游离脂肪酸（FAs）升高，饱和脂肪酸（如棕榈酸（PA））已被证明会增加宿主的炎症反应，我们试图找出PA如何与脂多糖（LPS）相互作用，以增强炎症，脂多糖是牙周病的一个重要病理因素。我们发现低浓度的LPS （1 ng/ml）刺激了RAW 264.7巨噬细胞中白细胞介素(IL)-6的表达，而PA进一步将其增强了4倍。除IL-6外，PA还放大了LPS对大量toll样受体（TLR） 4介导的促炎信号分子如IL-1受体相关激酶样2和促炎分子如单核细胞趋化蛋白-1和集落刺激因子的刺激作用。我们还观察到PA增强了TLR4而不是TLR2信号，并且这种增强是通过核因子κ B （nf - κ B）途径介导的。为了进一步阐明PA放大LPS信号的调控机制，我们的研究表明，PA和LPS通过刺激酸性鞘磷脂酶（ASMase）活性，协同增加鞘磷脂的水解，从而显著增加神经酰胺的产生和IL-6的上调。综上所述，本研究表明，PA显著增强了巨噬细胞中由低浓度LPS触发的tlr4介导的促炎信号，而ASMase在增强中起关键作用。
Periodontal disease is more prevalent and severe in patients with diabetes than in nondiabetic patients. In addition to diabetes, a large number of studies have demonstrated an association between obesity and chronic periodontal disease. However, the underlying mechanisms have not been well understood. Since plasma free fatty acids (FAs) are elevated in obese patients and saturated FAs such as palmitic acid (PA) have been shown to increase host inflammatory response, we sought to find out how PA interacts with lipopolysaccharide (LPS), an important pathological factor involved in periodontal disease, to enhance inflammation. We found that whereas low concentration of LPS (1 ng/ml) stimulated interleukin (IL)-6 expression in RAW 264.7 macrophages, PA further augmented it fourfold. Besides IL-6, PA amplified the stimulatory effect of LPS on a large amount of Toll-like receptor (TLR) 4-mediated expression of proinflammatory signaling molecules such as IL-1 receptor-associated kinase-like 2 and proinflammatory molecules, including monocyte chemotactic protein-1 and colony-stimulating factor. We also observed that PA augmented TLR4 but not TLR2 signal, and the augmentation was mediated by nuclear factor-kappa B (NF-kappa B) pathways. To further elucidate the regulatory mechanism whereby PA amplifies LPS signal, our studies showed that PA and LPS synergistically increased hydrolysis of sphingomyelin by stimulating acid sphingomyelinase (ASMase) activity, which contributed to a marked increase in ceramide production and IL-6 upregulation. Taken together, this study has demonstrated that PA markedly augments TLR4-mediated proinflammatory signaling triggered by low concentration of LPS in macrophages, and ASMase plays a key role in the augmentation.