Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Shanghai, 200031, China.
J Nutr. 2010 Feb;140(2):377-81. doi: 10.3945/jn.109.117804. Epub 2009 Dec 23.
The reaction of human leukocytes to chemoattractants is an important component of the host immune response and also plays a crucial role in the development of inflammation. Sesamin has been shown to inhibit lipid peroxidation and regulate cytokine production. In this study, we examined the effect of sesamin on inflammatory responses elicited by the bacterial chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (fMLF) in vitro and in vivo and explored the mechanisms involved. fMLF is recognized by a human G protein-coupled receptor formyl peptide receptor (FPR) on phagocytic leukocytes. Sesamin at concentrations between 12.5 and 50 micromol/L inhibited fMLF-induced chemotaxis of human monocyte cell line THP-1 differentiated with dibutyryl cyclic AMP (P < 0.01). Similarly, sesamin inhibited FPR-transfected rat basophilic leukemia cell [epitope-tagged human FPR (ETFR) cell] migration toward fMLF (P < 0.01). In fMLF-induced inflammation in a murine air-pouch model, intraperitoneal administration of sesamin (12 mgkg(-1)d(-1) for 2 d) suppressed leukocyte infiltration into the air pouch induced by fMLF [(62.89 +/- 7.93) x 10(4) vs. (19.67 +/- 4.43) x 10(4) cells/air pouch; n = 9; P < 0.001]. Ca(2+) mobilization and mitogen-activated protein kinase extracellular signal-regulated kinase (ERK1/2) activation are involved in fMLF-induced leukocyte migration. Pretreatment of ETFR cells with sesamin inhibited fMLF-induced ERK1/2 phosphorylation in a dose-dependent manner but did not affect fMLF-induced Ca(2+) flux. Electrophoretic mobility shift assay showed that pretreatment of THP-1 cells with sesamin dose dependently inhibited fMLF-induced nuclear factor-kappaB (NF-kappaB) activation. These results suggest that sesamin inhibits leukocyte activation by fMLF through ERK1/2- and NF-kappaB-related signaling pathways and thus is a potential compound for the management of inflammatory diseases.
芝麻素抑制趋化肽 fMLF 诱导的人白细胞反应及机制研究
探讨芝麻素对趋化肽 fMLF 诱导的人白细胞反应的抑制作用及其机制。
以人单核细胞株 THP-1 和转染人源 fMLF 受体(formyl peptide receptor，FPR)的大鼠嗜碱性白血病细胞[epitope-tagged human FPR(ETFR)细胞]为模型，观察芝麻素对 fMLF 诱导的细胞化学趋化运动的影响；建立小鼠气囊炎模型，观察芝麻素对 fMLF 诱导的白细胞渗出的影响；用[Ca(2+)]i 荧光探针和 Western blot 技术，观察芝麻素对 fMLF 诱导的细胞内钙离子浓度([Ca(2+)]i)变化和细胞外信号调节激酶 1/2(ERK1/2)磷酸化的影响；用凝胶电泳迁移率改变分析(EMSA)检测芝麻素对 fMLF 诱导的核因子-κB (NF-κB)核转位的影响。
芝麻素在 12.5～50 μmol/L 浓度范围内明显抑制 fMLF 诱导的 THP-1 细胞和 ETFR 细胞的化学趋化运动，其抑制率分别为 53.1%±10.1%和 53.2%±12.3%，并呈剂量依赖性(P<0.01)；在小鼠气囊炎模型，芝麻素(12 mg·kg(-1)·d(-1)，连续 2 d 腹腔注射)明显抑制 fMLF 诱导的白细胞渗出，抑制率为 74.0%±6.4%(n=9，P<0.001)；芝麻素能明显抑制 fMLF 诱导的 ETFR 细胞内[Ca(2+)]i 增加和 ERK1/2 磷酸化，对 fMLF 诱导的细胞内钙离子浓度变化无影响；芝麻素能明显抑制 fMLF 诱导的 NF-κB 核转位。
芝麻素通过 ERK1/2 和 NF-κB 信号通路抑制 fMLF 诱导的白细胞反应，在炎症性疾病的防治方面可能具有应用前景。
