Nagase Hiroyuki, Okugawa Shu, Ota Yasuo, Yamaguchi Masao, Tomizawa Hideyuki, Matsushima Kouji, Ohta Ken, Yamamoto Kazuhiko, Hirai Koichi
Department of Respiratory Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
J Immunol. 2003 Oct 15;171(8):3977-82. doi: 10.4049/jimmunol.171.8.3977.
We investigated the expression of a panel of Toll-like receptors (TLRs) and their functions in human eosinophils. Eosinophils constitutively expressed TLR1, TLR4, TLR7, TLR9, and TLR10 mRNAs (TLR4 greater than TLR1, TLR7, TLR9, and TLR10 greater than TLR6). In contrast, neutrophils expressed a larger variety of TLR mRNAs (TLR1, TLR2, TLR4, TLR6, TLR8 greater than TLR5, TLR9, and TLR10 greater than TLR7). Although the expression levels in eosinophils were generally less prominent compared with those in neutrophils, eosinophils expressed a higher level of TLR7. Furthermore, among various TLR ligands (S-(2,3-bis(palmitoyloxy)-(2-RS)-propyl)-N-palmitoyl-Cys-Ser-(Lys)(4), poly(I:C), LPS, R-848, and CpG DNA), only R-848, a ligand of TLR7 and TLR8, regulated adhesion molecule (CD11b and L-selectin) expression, prolonged survival, and induced superoxide generation in eosinophils. Stimulation of eosinophils by R-848 led to p38 mitogen-activated protein kinase activation, and SB203580, a p38 mitogen-activated protein kinase inhibitor, almost completely attenuated R-848-induced superoxide generation. Although TLR8 mRNA expression was hardly detectable in freshly isolated eosinophils, mRNA expression of TLR8 as well as TLR7 was exclusively up-regulated by IFN-gamma but not by either IL-4 or IL-5. The up-regulation of the TLRs by IFN-gamma had potentially functional significance: the extent of R-848-induced modulation of adhesion molecule expression was significantly greater in cells treated with IFN-gamma compared with untreated cells. Although the natural ligands for TLR7 and TLR8 have not yet been identified, our results suggest that eosinophil TLR7/8 systems represent a potentially important mechanism of a host-defensive role against viral infection and mechanism linking exacerbation of allergic inflammation and viral infection.
我们研究了一组Toll样受体（TLR）在人嗜酸性粒细胞中的表达及其功能。嗜酸性粒细胞组成性表达TLR1、TLR4、TLR7、TLR9和TLR10的mRNA（TLR4大于TLR1、TLR7、TLR9和TLR10大于TLR6）。相比之下，中性粒细胞表达的TLR mRNA种类更多（TLR1、TLR2、TLR4、TLR6、TLR8大于TLR5、TLR9和TLR10大于TLR7）。尽管嗜酸性粒细胞中的表达水平与中性粒细胞相比通常不那么显著，但嗜酸性粒细胞表达的TLR7水平更高。此外，在各种TLR配体（S-(2,3-双（棕榈酰氧基）-（2-RS）-丙基)-N-棕榈酰-Cys-Ser-(Lys)(4)、聚（I:C）、LPS、R-848和CpG DNA）中，只有R-848（TLR7和TLR8的配体）能调节嗜酸性粒细胞中黏附分子（CD11b和L-选择素）的表达、延长存活时间并诱导超氧化物生成。R-848刺激嗜酸性粒细胞导致p38丝裂原活化蛋白激酶激活，而p38丝裂原活化蛋白激酶抑制剂SB203580几乎完全减弱了R-848诱导的超氧化物生成。虽然在新鲜分离的嗜酸性粒细胞中几乎检测不到TLR8 mRNA的表达，但TLR8以及TLR7的mRNA表达仅由IFN-γ上调，而不由IL-4或IL-5上调。IFN-γ对TLR的上调具有潜在的功能意义：与未处理的细胞相比，用IFN-γ处理的细胞中R-848诱导的黏附分子表达调节程度明显更大。尽管尚未确定TLR7和TLR8的天然配体，但我们的结果表明，嗜酸性粒细胞TLR7/8系统代表了宿主抵抗病毒感染的防御作用以及连接过敏性炎症加重和病毒感染的潜在重要机制。
