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Am J Physiol Gastrointest Liver Physiol. 2018 Jul 1;315(1):G128-G139. doi: 10.1152/ajpgi.00027.2018. Epub 2018 Mar 15.

Protective effects of guggulsterone against colitis are associated with the suppression of TREM-1 and modulation of macrophages.

Che X1,2, Park KC2,3, Park SJ1, Kang YH1,2, Jin HA1,2, Kim JW4, Seo DH1,2, Kim DK5, Kim TI1, Kim WH1, Kim SW1,2,6, Cheon JH1,2,6.

Author information

1
Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine , Seoul , Korea.
2
Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine , Seoul , Korea.
3
Department of Surgery, Yonsei University College of Medicine , Seoul , Korea.
4
University of Toronto, Toronto, Ontario, Canada.
5
Chadwick International School , Seoul , Korea.
6
Severance Biomedical Science Institute, Yonsei University College of Medicine , Seoul , Korea.

Abstract

Triggering receptor expressed on myeloid cells 1 (TREM-1)-expressing intestinal macrophages are significantly increased in the colons of patients with inflammatory bowel disease (IBD). We focused here on the effects of guggulsterone on macrophage modulation in colitis as a potential therapeutic molecule in human IBD and explore the underlying mechanisms. Gene expression in macrophages was examined and wound-healing assay using HT-29 cells was performed. Colitis in wild-type and IL-10-, Toll-like receptor 4 (TLR4)-, and myeloid differentiation primary response 88 (MyD88)-deficient mice was induced via the administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) into the colon. In both in vitro and in vivo experiments, guggulsterone suppressed intestinal inflammation amplified by TREM-1 stimulation, in which the suppression of NF-κB, activating protein-1, and proteasome pathways was involved. In the TNBS-induced colitis model, guggulsterone reduced disease activity index scores and TREM-1 expression, stimulated IL-10 production, and improved survival in wild-type mice. These effects were not observed in IL-10-, TLR4-, and MyD88-deficient mice. Guggulsterone also suppressed M1 polarization, yet induced the M2 phenotype in macrophages from IBD patients as well as from mice. These findings indicate that guggulsterone blocks the hyperactivation of macrophages via TREM-1 suppression and induces M2 polarization via IL-10 mediated by the TLR4 signaling pathway. Furthermore, this study provides a new rationale for the therapeutic potential of guggulsterone in the treatment of IBD. NEW & NOTEWORTHY We found that guggulsterone attenuates triggering receptor expressed on myeloid cells 1 (TREM-1)-mediated hyperactivation of macrophages and polarizes macrophages toward the M2 phenotype. This was mediated by IL-10 and partly Toll-like receptor 4 signaling pathways. Overall, these data support that guggulsterone as a natural plant sterol modulates macrophage phenotypes in colitis, which may be of novel therapeutic importance in inflammatory bowel disease treatment.

KEYWORDS:

M2 macrophage; guggulsterone; inflammatory bowel disease; interleukin-10; triggering receptor expressed on myeloid cells 1

PMID:
29543509
DOI:
10.1152/ajpgi.00027.2018
[Indexed for MEDLINE]
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