Dose-dependent differential regulation of cytokine secretion from macrophages by fractalkine
Dose-dependent differential regulation of cytokine secretion from macrophages by fractalkine
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DOI：
10.4049/jimmunol.179.11.7478
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发表时间：
2007-12-01
影响因子：
4.4
通讯作者：
Dohi, Taeko
中科院分区：
文献类型：
--
作者：
Mizutani, Noriko;Sakurai, Toshiharu;Dohi, Taeko
尽管Fractalkine（CX 3CL 1，FKN）的表达在发炎组织中增强，但在稳态下在各种器官如肠中检测到，并且其受体CX 3CR 1在驻留型树突细胞和巨噬细胞中高度表达。我们推测FKN可能调节这些细胞的炎症反应。因此，用FKN预处理小鼠巨噬细胞，然后用LPS刺激。我们发现，用0.03 nM FKN预处理的巨噬细胞分泌的TNF-α比单独用LPS处理的细胞少50%，但用3 nM FKN预处理的巨噬细胞分泌的TNF-α却没有。用0.03 nM FKN和LPS处理的细胞也显示ERK 1/2磷酸化减少和NF-κ B p50亚基减少。有趣的是，NF-κ B B的p65亚基被易位到细胞核，但在早期通过与过氧化物酶体增殖物激活受体（PPAR）γ形成复合物而重新分布到细胞质。外源性15-脱氧-δ（12，14）-前列腺素J2（一种PPAR-gamma的天然配体）也诱导p65的再分布，在LPS刺激后TNF-α分泌减少。用0.03 nM但不是3 nM FKN预处理增加了15-脱氧-Delta（12，14）-前列腺素J2的细胞水平以及PPAR-gamma的mRNA。0.03 nM FKN的作用需要PPAR-gamma，通过PPAR-gamma的小干扰RNA证实。相比之下，与用0.03 nM FKN预处理的细胞相比，用3 nM FKN预处理诱导更高水平的IL-23，并以CX 3CR 1依赖性方式产生TNF-α。FKN的这些剂量依赖性差异效应确立了其在免疫稳态和炎症中的新作用。
Although expression of the fractalkine (CX3CL1, FKN) is enhanced in inflamed tissues, it is detected at steady state in various organs such as the intestine, and its receptor CX3CR1 is highly expressed in resident-type dendritic cells and macrophages. We hypothesized that FKN might regulate the inflammatory responses of these cells. Therefore, murine macrophages were pretreated with FKN and then stimulated with LPS. We found that macrophages pretreated with 0.03 nM FKN but not with 3 nM FKN secreted 50% less TNF-alpha than did cells treated with LPS alone. Cells treated with 0.03 nM FKN and LPS also showed reduced phosphorylation of ERK1/2 and reduced NF-kappa B p50 subunit. Interestingly, the p65 subunit of NF-kappa B was translocated to the nuclei but redistributed to the cytoplasm in the early phase by forming a complex with peroxisome proiliferator-activated receptor (PPAR) gamma. Exogenous 15-deoxy-Delta(12,14)-prostaglandin J2, a natural ligand for PPAR-gamma, also induced redistribution of p65 with decreased TNF-a secretion after LPS challenge. Pretreatment with 0.03 nM but not 3 nM FKN increased the cellular-levels of 15-deoxy-Delta(12,14)-prostaglandin J2 as well as mRNA of PPAR-gamma. Requirement of PPAR-gamma for the effect of 0.03 nM FKN was confirmed by small interfering RNA of PPAR-gamma. In contrast, pretreatment with 3 nM FKN induced higher levels of IL-23 compared with cells pretreated with 0.03 nM FKN and produced TNF-alpha in a CX3CR1-dependent manner. These dose-dependent differential effects of FKN establish its novel role in immune homeostasis and inflammation.