Gamma interferon and granulocyte/monocyte colony-stimulating factor prevent endotoxin tolerance in human monocytes by promoting interleukin-1 receptor-associated kinase expression and its association to MyD88 and not by modulating TLR4 expression
Gamma interferon and granulocyte/monocyte colony-stimulating factor prevent endotoxin tolerance in human monocytes by promoting interleukin-1 receptor-associated kinase expression and its association to MyD88 and not by modulating TLR4 expression
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DOI：
10.1074/jbc.m200705200
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发表时间：
2002-08-02
影响因子：
4.8
通讯作者：
Cavaillon, JM
中科院分区：
文献类型：
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作者：
Adib-Conquy, M;Cavaillon, JM
内毒素耐受的特征是培养的白细胞在第一次暴露于相同的刺激后，对脂多糖(LPS)的反应减少了促炎症细胞因子的产生。干扰素(IFN)和粒/单核细胞集落刺激因子(GM-CSF)是一种免疫刺激性细胞因子，可激活单核细胞，防止内毒素耐受。在这项研究中，我们表明，内毒素的失活作用以及IFNGamma和GM-CSF的启动效应或它们恢复内毒素耐受的人单核细胞产生肿瘤坏死因子(TNF)的能力与TLR2、TLR4或MD-2的调节无关。单核细胞经IFNGamma或GM-CSF处理后，白细胞介素1受体相关激酶(IRAK)的表达上调。内毒素刺激后，IRAK活性增加，MyD88/IRAK结合增强，核因子-kappaB活性增强。相反，在内毒素耐受的单核细胞中，IRAK的表达和激酶活性、IRAK/MyD88的结合和核因子-kappaB的激活都受到抑制。此外，IFNGamma和GM-CSF对耐受的预防作用不依赖IRAK激酶活性。我们的结果表明，这些细胞因子通过抑制IRAK的降解，并在第二次内毒素刺激后促进其与MyD88的联系，从而阻止低剂量而不是高剂量内毒素诱导的内毒素耐受，进而导致核因子-kappaB的激活和肿瘤坏死因子的产生。
Endotoxin tolerance is characterized by a decreased production of proinflammatory cytokines by cultured leukocytes in response to lipopolysaccharide (LPS) following a first exposure to the same stimulus. Gamma interferon (IFNgamma) and granulocyte/monocyte colony-stimulating factor (GM-CSF) are immunostimulatory cytokines that prime monocytes and prevent endotoxin tolerance. In this study, we show that the deactivating effects of LPS, as well as the priming effects of IFNgamma and GM-CSF or their capacity to restore tumor necrosis factor (TNF) production by LPS-tolerized human monocytes are independent of the modulation of TLR2, TLR4, or MD-2. In monocytes pretreated with IFNgamma or GM-CSF, interleukin-1 receptor-associated kinase (IRAK) expression is up-regulated. After LPS stimulation, an increased IRAK kinase activity, a higher MyD88/IRAK association, and a stronger NF-kappaB activation are observed. In contrast, in LPS-tolerized monocytes, IRAK expression and kinase activity, IRAK/MyD88 association, and NF-kappaB activation are inhibited. Furthermore the prevention of tolerance by IFNgamma and GM-CSF was independent of IRAK kinase activity. Our results suggest that these cytokines prevent endotoxin tolerance induced by low but not by high doses of LPS by inhibiting IRAK degradation and by promoting its association with MyD88 after a second LPS stimulation, which in turn leads to NF-kappaB activation and TNF production.