Role of innate immune factors in the adjuvant activity of monophosphoryl lipid A
Role of innate immune factors in the adjuvant activity of monophosphoryl lipid A
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DOI：
10.1128/iai.71.5.2498-2507.2003
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发表时间：
2003-05-01
影响因子：
3.1
通讯作者：
Katz, J
中科院分区：
文献类型：
--
作者：
Martin, M;Michalek, SM;Katz, J
单磷酰脂质A（MPL）是脂多糖（LPS）的无毒衍生物，其表现出与母体LPS分子相似的佐剂性质。然而，MPL启动其免疫刺激特性的机制仍不清楚。由于Toll样受体参与识别和转导细胞内信号以响应LPS，本研究的目的是确定MPL利用Toll样受体2（TLR 2）和TLR 4的能力。我们提供的证据表明，MPL差异利用TLR 2和TLR 4诱导肿瘤坏死因子α，白细胞介素10（IL-10）和IL-12的纯化的人单核细胞以及人外周血单核细胞。对NF-κ B活性的评估表明，MPL利用TLR 2，尤其是TLR 4通过人单核细胞激活NF-κ B p65。此外，MPL对人单核细胞的刺激导致共刺激分子CD 80和CD 86的上调，这种作用可以通过用TLR 2或TLR 4的单克隆抗体预处理细胞来降低。对MPL诱导的细胞外信号调节激酶（ERK）和p38丝裂原活化蛋白（MAP）激酶活化的分析表明，MPL利用TLR 2和TLR 4进行ERK 1/2的磷酸化，而TLR 4是MPL磷酸化p38能力的主要受体。此外，使用MAP激酶激酶（PD 98059）和p38（SB 203580）的选择性抑制剂，我们表明ERK 1/2对TNF-α的产生表现出不同的影响。和IL-12 p40，而MPL-induced p38的激活似乎主要参与MPL-stimulated单核细胞产生IL-10和IL-12 p40。总之，这些发现有助于理解MPL诱导宿主细胞活化和随后佐剂性质的细胞机制。
Monophosphoryl lipid A (MPL) is a nontoxic derivative of lipopolysaccharide (LPS) that exhibits adjuvant properties similar to those of the parent LPS molecule. However, the mechanism by which MPL initiates its immunostimulatory properties remains unclear. Due to the involvement of Toll-like receptors in recognizing and transducing intracellular signals in response to LPS, the aim of the present study was to determine the ability of MPL to utilize the Toll-like receptor 2 (TLR2) and TLR4. We provide evidence that MPL differentially utilizes TLR2 and TLR4 for the induction of tumor necrosis factor alpha, interleukin 10 (IL-10), and IL-12 by purified human monocytes as well as by human peripheral blood mommuclear cells. Assessment of NF-kappaB activity demonstrated that MPL utilized TLR2 and especially TLR4 for the activation of NF-kappaB p65 by human monocytes. In addition, stimulation of human monocytes by MPL led to an up-regulation of the costimulatory molecules CD80 and CD86, an effect that could be reduced by pretreatment of cells with a monoclonal antibody to TLR2 or TLR4. Analysis of MPL-induced activation of the extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein (MAP) kinases revealed that MPL utilized both TLR2 and TLR4 for the phosphorylation of ERK1/2, while TLR4 was the predominant receptor involved in the ability of MPL to phosphorylate p38. Moreover, using selective inhibitors for MAP kinase kinase (PD98059) and p38 (SB203580), we show that ERK1/2 exhibited differential effects on production of TNF-alpha. and IL-12 p40 by human monocytes, whereas MPL-induced activation of p38 appeared to be predominantly involved in production of IL-10 and IL-12 p40 by MPL-stimulated monocytes. Taken together, these findings aid in understanding the cellular mechanisms by which MPL induces host cell activation and subsequent adjuvant properties.