Department of Cardiology, Xiangya Hospital, Central South University, Changsha 410008, China.
Department of Geriatric Cardiology, Xiangya Hospital, Central South University, Changsha 410008, China.
J Cell Biochem. 2018 Jul;119(7):5072-5081. doi: 10.1002/jcb.26227. Epub 2018 Mar 25.
Nucleotide-binding oligomerization domain containing 2 (NOD2)-induced signal transduction and cytokine production is regulated by a number of factors. However, the feedback effect of the pro-inflammatory TNF-α on NOD2-induced inflammation is not fully understood. In this study, we found unexpectedly that TNF-α up-regulated NOD2 ligand MDP-induced production of the CXC chemokines, including CXCL1, 2, and 8, and the pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α, in a dose-dependent manner at both mRNA and protein levels in monocytic THP-1 cells. Though TNF-α induced the up-regulation of ubiquitin-editing enzyme A20, an important negative regulator for Toll-like receptor- and NOD2-induced inflammatory responses, the over-expression of A20 by gene transfer did not reversed MDP-induced production of cytokines, suggested that A20 did not regulate the functions of NOD2 in THP-1 cells. Meanwhile, we found that TNF-α up-regulated NOD2 and its down-stream adaptor protein RIP2 at both mRNA and protein levels. MDP induced the activation of ERK, JNK, p38 and NF-κB, and TNF-α pre-treatment augmented this activation. The results from pharmacological inhibition assay showed that cytokine production was dependent on MAPK signaling. In addition, we found that the pre-treatment of THP-1 cells with MDP down-regulated the mRNA levels of cytokine induced by MDP re-treatment. MDP pre-treatment up-regulated NOD2, but down-regulated RIP2, and down-regulated NOD2 signal transduction induced by MDP re-stimulation. Taking together, these results suggested that TNF-α is a positive regulator for NOD2 functions via up-regulation of NOD2 and its signal adaptor RIP2, and TNF-α-induced A20 does not regulate MDP-induced inflammatory responses in THP-1 cells. J. Cell. Biochem. 119: 5072-5081, 2018. © 2017 Wiley Periodicals, Inc.
核苷酸结合寡聚化结构域 2（NOD2）诱导的信号转导和细胞因子产生受到许多因素的调节。然而，促炎细胞因子 TNF-α 对 NOD2 诱导的炎症的反馈作用尚未完全阐明。在这项研究中，我们出人意料地发现，TNF-α 以剂量依赖的方式在上调单核细胞 THP-1 细胞中 NOD2 配体 MDP 诱导的 CXC 趋化因子（包括 CXCL1、2 和 8）和促炎细胞因子（包括 IL-1β、IL-6 和 TNF-α）的产生方面具有上调作用。虽然 TNF-α 诱导泛素编辑酶 A20 的上调，A20 是 Toll 样受体和 NOD2 诱导的炎症反应的重要负调节因子，但通过基因转移过表达 A20 并不能逆转 MDP 诱导的细胞因子产生，表明 A20 并未调节 NOD2 在 THP-1 细胞中的功能。同时，我们发现 TNF-α 上调了 NOD2 及其下游衔接蛋白 RIP2 的 mRNA 和蛋白水平。MDP 诱导 ERK、JNK、p38 和 NF-κB 的激活，而 TNF-α 预处理增强了这种激活。药理抑制试验的结果表明细胞因子的产生依赖于 MAPK 信号通路。此外，我们发现 MDP 预处理可下调 MDP 再处理诱导的细胞因子的 mRNA 水平。MDP 预处理上调 NOD2，但下调 RIP2，并下调 MDP 再刺激诱导的 NOD2 信号转导。综上所述，这些结果表明 TNF-α 通过上调 NOD2 和其信号衔接蛋白 RIP2 成为 NOD2 功能的正调节剂，而 TNF-α 诱导的 A20 并不调节 THP-1 细胞中 MDP 诱导的炎症反应。J. Cell. Biochem. 119: 5072-5081, 2018. © 2017 Wiley Periodicals, Inc.
