ZAP70 deficiency promotes reverse cholesterol transport through MAPK/ERK pathway in Jurkat cell

• Published in: Molecular immunology 2019-03, Vol.107, p.21-28
• Main Authors: Liu, Jichen, Guo, Kai, Hu, Lu, Luo, Tiantian, Ma, Yusheng, Zhang, Yanan, Lai, Wenyan, Guo, Zhigang
• Format: Article
• Language: English
• Subjects: ERK; Reverse cholesterol transport; T cells; ZAP70
• ISSN: 0161-5890; 1872-9142
• DOI: 10.1016/j.molimm.2019.01.001

•We found ZAP70-deficiency reduced mRNA expression and secretion of TNF-α, IFN-γ, IL-2 and IL-6.•ZAP70-deficiency improved cholesterol efflux capacity and increased expression of ABCA1, ABCG1 and SR-BI.•Phosphorylation of ERK, JNK and p38 MAPK were inhibited due to lack of ZAP70.•Only the ERK inhibitor was observed to improved cholesterol efflux capacity and increased expression of ABCA1, ABCG1 and SR-BI. Inhibiting JNK or p38 MAPK didn’t affect cholesterol efflux capacity or RCT regulatory proteins.•Inhibiting ERK increased the interaction between LXR protein and the LXRE which promoted ABCG1 expression without increasing the amount of LXR-α. Lots of studies have demonstrated that immune cells could regulate reverse cholesterol transport (RCT). However, neither T cell receptor (TCR) signalling nor Zeta-chain associated protein 70 (ZAP70) have been demonstrated to be associated with RCT. To investigate this association, we used a ZAP70-deficient Jurkat-derived mutant, P116 cell line, to detect the effect of ZAP70 on RCT and inflammatory response. ZAP70 deficiency improved cholesterol efflux capacity by 14%. Meanwhile, mRNA and proteins expression of RCT regulatory proteins such as ABCA1, ABCG1 and SR-BI were increased in P116 cells. ZAP70-deficiency had no influence on LXR-α and PPAR-γ. Regarding the inflammatory response, the mRNA expression and secretion of pro-atherosclerotic cytokines, TNF-α, IFN-γ, IL-2 and IL-6, were significantly decreased in the ZAP70-deficient cell line. Activation of MAP kinases cascades, as determined by of ERK, JNK and p38 MAPK phosphorylation, were found to be inhibited in the absence of ZAP70. Specific inhibition of ERK, JNK and p38 MAPK activity was also found to decreased TNF-α, IFN-γ, and IL-6 secretion. However, only the ERK inhibition was observed to reduce IL-2 secretion, improve cholesterol efflux capacity and increase expression of ABCA1, ABCG1 and SR-BI without increasing LXR-α and PPAR-γ. Using ChIP assay to detect the binding of LXR-α to LXRE, which promotes the expression of ABCG1, we found that inhibiting ERK improved binding without increasing LXR-α levels. Thus, we speculate that ZAP70-deficiency may improve RCT and decrease the inflammatory response of T cells. Furthermore, these effects are probably achieved via ERK signalling pathway.