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TNF‐α‐Induced NOD2 and RIP2 Contribute to the Up‐Regulation of Cytokines Induced by MDP in Monocytic THP‐1 Cells
Author(s) -
Chen Xiaobin,
Xiao Zhilin,
Xie Xiumei,
Liu Xueting,
Jiang Manli,
Yuan Chuang,
Yang Li,
Hu Jinyue
Publication year - 2018
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.26227
Subject(s) - nod2 , thp1 cell line , cytokine , proinflammatory cytokine , signal transduction , microbiology and biotechnology , tumor necrosis factor alpha , chemokine , chemistry , mapk/erk pathway , regulator , signal transducing adaptor protein , inflammation , biology , receptor , immunology , cell culture , biochemistry , innate immune system , gene , genetics
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.