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.