Department of Medicine, Yale University, New Haven, Connecticut, USA.
Gastroenterology. 2012 Dec;143(6):1530-43. doi: 10.1053/j.gastro.2012.08.048. Epub 2012 Sep 8.
BACKGROUND & AIMS: 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 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. Importantly, 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.
核苷酸结合寡聚化结构域包含蛋白 2（Nod2）和其他模式识别受体（PRR）在人单核细胞衍生的巨噬细胞中的刺激诱导白细胞介素（IL）-1 的产生，这增加了丝裂原活化蛋白激酶（MAPK）的激活和细胞因子的分泌。PRR 对 MAPK 的激活对炎症细胞因子分泌有不同的影响。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影响。
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。我们过表达或减少 MAPK 水平（使用小干扰 RNA）。
Nod2 和其他 PRR 通过细胞外信号相关激酶（ERK）和 p38 激活信号，抑制人单核细胞衍生的巨噬细胞中炎症细胞因子的产生；自分泌的 IL-1 产生阻止了这种抑制。ERK 和 p38 抑制产生低水平 IL-1 的人巨噬细胞（如 M2、内毒素耐受和肠道巨噬细胞）中炎症细胞因子的产生；添加外源性 IL-1 导致 ERK 和 p38 在这些细胞中刺激炎症细胞因子的产生。在单独用 PRR 刺激时不会产生 IL-1 的小鼠巨噬细胞中，添加外源性 IL-1 逆转了 ERK 介导的对 IL-12p40 的抑制。在 Nod2 刺激的人单核细胞衍生的巨噬细胞中，增加 c-Jun N 末端激酶的激活，在没有自分泌 IL-1 信号的情况下，导致 ERK 和 p38 刺激炎症细胞因子的分泌。重要的是，感染诱导 IL-1 产生的人类肠道巨噬细胞的病原体逆转了 ERK 和 p38 对炎症细胞因子产生的抑制。
在巨噬细胞对 PRR 刺激的反应中，MAPK 信号的水平受到自分泌 IL-1 的调节，并决定了炎症细胞因子的产生是被抑制还是被刺激。这种机制可以解释报道的 MAPK 对炎症细胞因子调节的差异，并传播对病原体的炎症反应。
