Department of Cardiology, Changsha Central Hospital, Changsha, China.
Graduate School, University of South China, Hengyang, China.
Lab Invest. 2019 Sep;99(9):1321-1334. doi: 10.1038/s41374-019-0252-7. Epub 2019 Apr 24.
Both toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) induce a tightly regulated inflammatory response at risk of causing tissue damage, depending on the effectiveness of ensuing negative feedback regulatory mechanisms. Cross-regulation between TLRs, NLRs, and cytokine receptors has been observed. However, the cross-regulation between interleukin-1 (IL-1) receptors and NOD2 is not completely understood. In this study, we found that IL-1α/β increased NOD2-induced inflammatory response in human monocytic THP1 cells, peripheral blood mononuclear cells (PBMCs), mouse macrophage RWA264.7 cells and spleen cells, and in an in vivo experiment. IL-1α/β pre-treatment induced the production of CXC chemokines, including growth-regulated oncogene (GRO)-α, GRO-β, and IL-8, and proinflammatory cytokines, including IL-1β, IL-6, and TNFα, which are induced by the activation of NOD2, in a dose- and time-dependent manner. However, pre-treatment with the NOD2 ligand muramyl dipeptide (MDP) did not up-regulate the expression of cytokines induced by IL-1α/β re-treatment. IL-1β treatment increased the expression of A20, which is an important inhibitor of the innate immune response. However, the overexpression of A20 failed to inhibit MDP-induced cytokine production, suggesting that A20 had no effects on the NOD2-induced immune response. In addition, IL-1α/β increased the expression of NOD2 and its downstream adaptor RIP2, and IL-1α/β pre-treatment increased MDP-induced activation of mitogen-activated protein kinases (MAPKs), including ERK, JNK, and P38, which contributed to MDP-induced cytokine production. Based on these results, IL-1α/β promote the NOD2-induced immune responses by enhancing MDP-induced activation of MAPK signaling pathways.
TLR 和 NOD 样受体 (NLR) 均可诱导严格调控的炎症反应，但其可能导致组织损伤，这取决于后续负反馈调节机制的有效性。已经观察到 TLR、NLR 和细胞因子受体之间的交叉调节。然而，白细胞介素 1 (IL-1) 受体和 NOD2 之间的交叉调节尚不完全清楚。在这项研究中，我们发现 IL-1α/β 增强了人单核细胞 THP1 细胞、外周血单核细胞 (PBMC)、鼠巨噬细胞 RWA264.7 细胞和脾细胞中以及体内实验中 NOD2 诱导的炎症反应。IL-1α/β 预处理以剂量和时间依赖的方式诱导 CXC 趋化因子（包括生长调节致癌基因-α[GRO-α]、GRO-β 和 IL-8）和促炎细胞因子（包括 IL-1β、IL-6 和 TNFα）的产生，这些细胞因子由 NOD2 的激活诱导。然而，NOD2 配体 muramyl dipeptide (MDP) 的预处理不能上调 IL-1α/β 再处理诱导的细胞因子表达。IL-1β 处理增加了先天免疫反应的重要抑制剂 A20 的表达。然而，A20 的过表达未能抑制 MDP 诱导的细胞因子产生，表明 A20 对 NOD2 诱导的免疫反应没有影响。此外，IL-1α/β 增加了 NOD2 及其下游衔接蛋白 RIP2 的表达，IL-1α/β 预处理增加了丝裂原活化蛋白激酶 (MAPK)，包括 ERK、JNK 和 P38 的激活，这有助于 MDP 诱导的细胞因子产生。基于这些结果，IL-1α/β 通过增强 MAPK 信号通路的激活来促进 NOD2 诱导的免疫反应。
