Discussion
UC is one of the main types of IBD which is affect the
bowel5 and it could develop into colorectal
cancer(CRC)7. EGCG is a major compound of
tea9 and it could attenuate colitis in UC
mice10. However, the mechanism of EGCG in the
treatment of colitis should be further investigated. A previous study
reported that regulation Notch signaling pathway could enhance
intestinal barrier function in colitis mice4 and it
could be a target of chronic inflammatory diseases, such as
IBD6. In our previous studies, we reported that Notch
is a receptor of EGCG11,17. In this study, we focused
on the Notch signaling pathway which plays a role in the development of
UC and aberrant activation of Notch1 was attributed to the severity of
CRC18. Our results found that the inflammation state
and Notch expression were altered by EGCG treatment in Caco-2 cell which
induced by LPS. Furthermore, we also identified the mechanism is present
in UC mice, which is induced by DSS in C57/BL6 mice. These results
suggested that EGCG could play a role to against colitis by regulation
Notch signaling pathway in UC mice.
Previous studies have been reported that Notch could regulation
inflammation19,20 and modulates macrophages
polarization21. Some studies also propose that
targeting the Notch signaling pathway could be a potential therapeutic
strategy to improve chronic inflammatory
diseases6,22,23. A new research reported that the
transcription levels of Notch1 and Hes-1 genes were significantly
elevated in UC patients22 which reminder us to reflect
on important of Notch in UC. And recent studies have revealed the
unexpected importance of epithelial cells in the pathophysiology of
IBD24. So, in this study, we take human epithelial
colorectal adenocarcinoma Caco-2 cell line as inflammation
model25 to assess the inflammatory responds with LPS
treatment. Our research found that the inflammation responds was
increased by LPS treatment in Caco-2 cell (figure 1A and 1B) or enhance
intestinal immune response in DSS induced UC mice colon (figure3 and
figure 4). And the levels of Notch1 and cleaved-Notch1 expression were
also increase by LPS treatment in Caco-2 cell (figure 1D) or DSS induced
UC mice colon. These results was similar to the previous study
report22,26,27. And our finding also showed that Notch
could be a target to therapy hyper-inflammatory respond and UC.
Moreover, this research also proved that Notch activate could contribute
to M1 macrophages accumulation. These founds suggest that activate Notch
play a role to induced UC as other studies
report7,8,22.
The effect of EGCG on perfect IBD has been reported in previous
studies28,29. And our previous studies have been
demonstration that Notch was a target of EGCG11,30 to
attenuate inflammation responds or other chronic
disease17. So, we think the Notch maybe was a target
of EGCG to attenuate UC. In this study, we found that EGCG could
decreased the cytokine level which induced by LPS in Caco-2 cell (figure
1A and 1B). The levels of Notch expression were increased and Notch was
activation by LPS stimulation in cell, but, the phenomenon was
disappeared by administration EGCG in vitro (figure 1D). Moreover, the
inflammation state of colon and macrophages accumulation were also
decreased by oral EGCG (figure 3 and figure 4). To further understand
the mechanism of EGCG on attenuate colitis, we detected Notch signaling
protein and found that the level of Notch expression, Notch activation,
and downstream protein were also significance decreased by
administration EGCG (figure 5). Our results revealed the effect of EGCG
on UC and expound the mechanism.
In conclusion, our study provides direct evidence that EGCG reduces
inflammatory response by targeting Notch and reveals the mechanism by
which EGCG alleviates colitis in UC mice (Figure 6). EGCG suppressing
inflammation may be a promising treatment option for chronic
inflammatory diseases in patients with IBD.