Nod2-induced autocrine interleukin-1 alters signaling by ERK and p38 to differentially regulate secretion of inflammatory cytokines.
Nod2-induced autocrine interleukin-1 alters signaling by ERK and p38 to differentially regulate secretion of inflammatory cytokines.
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DOI：
10.1053/j.gastro.2012.08.048
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发表时间：
2012-12
期刊：
影响因子：
29.4
通讯作者：
Abraham C
中科院分区：
文献类型：
--
作者：
Hedl M;Abraham C
刺激人单核细胞源性巨噬细胞中含核苷酸结合寡聚化结构域（Nod）2和其他模式识别受体（PRR）可诱导白细胞介素（IL）-1，从而增加丝裂原活化蛋白激酶（MAPK）活化和细胞因子分泌。不同PRR激活MAPK对炎性细胞因子分泌的影响不同。我们研究了不同水平的自分泌IL-1是否介导了这些不同的效应。通过酶联免疫吸附试验和流式细胞术分析巨噬细胞对PRR配体的反应。我们过表达或降低MAPK水平（使用小抑制RNA）。Nod 2和其他PRR通过细胞外信号相关激酶（ERK）和p38激活信号传导，抑制人单核细胞衍生的巨噬细胞产生炎性细胞因子;自分泌IL-1的产生阻止了这种抑制。ERK和p38抑制产生低水平IL-1的人类巨噬细胞（例如M2、内毒素耐受和肠道巨噬细胞）产生炎症细胞因子;添加外源性IL-1会导致ERK和p38刺激这些细胞中炎症细胞因子的产生。在小鼠巨噬细胞中，不产生IL-1在PRR刺激单独响应，添加外源性IL-1逆转ERK介导的抑制IL-12 p40。在没有自分泌IL-1信号的情况下，Nod 2刺激的人单核细胞衍生的巨噬细胞中c-Jun N-末端激酶的激活增加，导致ERK和p38刺激炎性细胞因子分泌。感染人类肠道巨噬细胞的病原体，诱导IL-1的生产逆转抑制炎症细胞因子的生产ERK和p38。响应于巨噬细胞的PRR刺激，MAPK信号传导的水平由自分泌IL-1调节，并决定炎性细胞因子的产生是被抑制还是被刺激。这种机制可以解释所报道的炎症细胞因子的MAPK调节的差异，并传播对病原体的炎症反应。
Stimulation of nucleotide-binding oligomerization domain-containing (Nod)2 and other pattern recognition receptors (PRR) in human monocyte-derived macrophages induces interleukin (IL)-1, which increases mitogen-activated protein kinase (MAPK) activation and cytokine secretion. Activation of MAPK by different PRR has varied effects on inflammatory cytokine secretion. We investigated whether different levels of autocrine IL-1 mediate these varied effects. Macrophage responses to PRR ligands were analyzed by enzyme-linked immunosorbent assay and flow cytometry. We overexpressed or reduced MAPK levels (using small inhibitory RNA). Nod2 and other PRR activated signaling via extracellular signal-related kinase (ERK) and p38 that inhibited inflammatory cytokine production by human monocyte-derived macrophages; autocrine IL-1 production prevented this inhibition. ERK and p38 inhibited inflammatory cytokine production by human macrophages that produce low levels of IL-1 (such as M2, endotoxin-tolerant, and intestinal macrophages); adding exogenous IL-1 caused ERK and p38 to stimulate production of inflammatory cytokines in these cells. In mouse macrophages, which do not produce IL-1 in response to PRR stimulation alone, addition of exogenous IL-1 reversed the ERK-mediated inhibition of IL-12p40. Increasing activation of c-Jun N-terminal kinase in Nod2-stimulated human monocyte-derived macrophages, in the absence of autocrine IL-1 signaling, caused ERK and p38 to stimulate inflammatory cytokines secretion. Infection of human intestinal macrophages with pathogens that induce IL-1 production reversed the inhibition of inflammatory cytokine production by ERK and p38. In response to PRR stimulation of macrophages, the level of MAPK signaling is regulated by autocrine IL-1 and determines whether production of inflammatory cytokines is inhibited or stimulated. This mechanism could account for reported differences in MAPK regulation of inflammatory cytokines and propagate the inflammatory response to pathogens.
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