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* = Presenting author

P016 Guggulsterone ameliorates colitis by suppressing TREM-1 hyperactivation and modulating macrophage phenotypes

X. Che*1, 2, K. C. Park3, S. J. Park1, 4, Y. H. Kang1, H. A. Jin1, 2, D. H. Seo1, 2, S. W. Kim1, 2, 4, T. I. Kim1, W. H. Kim1, J. H. Cheon1, 2, 4

1Yonsei University, Internal Medicine and Institute of Gastroenterology, Seoul, South Korea, 2Yonsei University, Brain Korea 21 PLUS Project for Medical Science, Seoul, South Korea, 3Yonsei University, Seoul, South Korea, 4Severance Biomedical Science Institute, Seoul, South Korea

Background

Macrophages are important immune cells in chronic and acute inflammation environment, which modulate their phenotype according to environment to kill pathogens or repair injured tissue. Triggering receptor expressed on myeloid cells (TREM)-1 is constitutively expressed in macrophages, is upregulated by bacterial components such as lipopolysaccharide (LPS), and functions as an amplifying molecule in inflammatory responses. In this study, we investigated the anti-inflammatory effects of natural plant sterol (GGS), via the inhibition of NF-κB/TREM-1 and TNBS-induced colitis models. Moreover, we draw attention to the function of GGS in polarising macrophage.

Methods

RAW264.7 macrophage-like cells were stimulated with lipopolysaccharide (LPS) in the presence or absence of GGS. The effect of GGS on NF-κB signalling and TREM-1 associated protein levels were examined by Western blotting and ELISA and nuclear translocation using immunofluorescence. The mRNA levels of macrophage phenotype markers were checked using real time RT-polymerase chain reaction (PCR). Mouse colitis was induced by the administration of TNBS into the colon and disease activity index and mouse survival rate were checked.

Results

GGS treatment decreased the protein levels of TREM-1, TLR4, TNF-α, IL-6, IL17, COX-2, and MMP-9 by blocking the phosphorylation and degradation of IκB, as well as nuclear translocation of NF-κB, in RAW264.7 cells activated by LPS. In addition, GGS increased the mRNA levels of M2-like phenotype markers, whereas it decreased M1-like phenotype markers in both RAW264.7 cells and bone marrow–derived macrophages (BMDMs). In the TNBS-induced colitis model, GGS reduced disease activity index, inflammation-related protein expressions by suppressing NF-κB and TREM-1 activation in the colon mucosa. In addition, it improved mouse survival rate in wild-type mice, but not in Il10 or Tlr4 deficient mice.

Conclusion

GGS blocked the NF-κB signalling pathway by targeting TREM-1 in RAW264.7 cells activated by LPS and ameliorated TNBS-induced mouse colitis. Further, GGS polarised macrophage towards an M2 anti-inflammatory phenotype in RAW264.7 cells. These findings suggest that GGS is a potential therapeutic agent for the treatment of IBD.