Sweet Matthew J, Campbell Carol C, Sester David P, Xu Damo, McDonald Rebecca C, Stacey Katryn J, Hume David A, Liew Foo Y
Department of Immunology and Bacteriology, University of Glasgow, Glasgow, United Kingdom.
J Immunol. 2002 Jan 1;168(1):392-9. doi: 10.4049/jimmunol.168.1.392.
During bacterial infections, the balance between resolution of infection and development of sepsis is dependent upon the macrophage response to bacterial products. We show that priming of murine bone marrow-derived macrophages (BMMs) with CSF-1 differentially regulates the response to two such stimuli, LPS and immunostimulatory (CpG) DNA. CSF-1 pretreatment enhanced IL-6, IL-12, and TNF-alpha production in response to LPS but suppressed the same response to CpG DNA. CSF-1 also regulated cytokine gene expression in response to CpG DNA and LPS; CpG DNA-induced IL-12 p40, IL-12 p35, and TNF-alpha mRNAs were all suppressed by CSF-1 pretreatment. CSF-1 pretreatment enhanced LPS-induced IL-12 p40 mRNA but not TNF-alpha and IL-12 p35 mRNAs, suggesting that part of the priming effect is posttranscriptional. CSF-1 pretreatment also suppressed CpG DNA-induced nuclear translocation of NF-kappaB and phosphorylation of the mitogen-activated protein kinases p38 and extracellular signal-related kinases-1/2 in BMMs, indicating that early events in CpG DNA signaling were regulated by CSF-1. Expression of Toll-like receptor (TLR)9, which is necessary for responses to CpG DNA, was markedly suppressed by CSF-1 in both BMMs and thioglycolate-elicited peritoneal macrophages. CSF-1 also down-regulated expression of TLR1, TLR2, and TLR6, but not the LPS receptor, TLR4, or TLR5. Hence, CSF-1 may regulate host responses to pathogens through modulation of TLR expression. Furthermore, these results suggest that CSF-1 and CSF-1R antagonists may enhance the efficacy of CpG DNA in vivo.
在细菌感染期间，感染的消退与败血症的发展之间的平衡取决于巨噬细胞对细菌产物的反应。我们发现，用集落刺激因子-1（CSF-1）预处理小鼠骨髓来源的巨噬细胞（BMMs），会差异性地调节对两种此类刺激物，即脂多糖（LPS）和免疫刺激（CpG）DNA的反应。CSF-1预处理增强了BMMs对LPS刺激的白细胞介素-6（IL-6）、白细胞介素-12（IL-12）和肿瘤坏死因子-α（TNF-α）的产生，但抑制了对CpG DNA的相同反应。CSF-1还调节了BMMs对CpG DNA和LPS刺激的细胞因子基因表达；CSF-1预处理抑制了CpG DNA诱导的IL-12 p40、IL-12 p35和TNF-α mRNA的表达。CSF-1预处理增强了LPS诱导的IL-12 p40 mRNA的表达，但未增强TNF-α和IL-12 p35 mRNA的表达，这表明部分预处理效应是转录后水平的。CSF-1预处理还抑制了CpG DNA诱导的BMMs中核因子κB（NF-κB）的核转位以及丝裂原活化蛋白激酶p38和细胞外信号调节激酶-1/2（ERK-1/2）的磷酸化，这表明CSF-1调节了CpG DNA信号传导的早期事件。在BMMs和巯基乙酸盐诱导的腹腔巨噬细胞中，CSF-1均显著抑制了对CpG DNA反应所必需的Toll样受体9（TLR9）的表达。CSF-1还下调了TLR1、TLR2和TLR6的表达，但未下调LPS受体TLR4或TLR5的表达。因此，CSF-1可能通过调节TLR表达来调节宿主对病原体的反应。此外，这些结果表明CSF-1和CSF-1R拮抗剂可能会增强CpG DNA在体内的疗效。
