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

 Xiumei Che  ;  Ki Cheong Park  ;  Soo Jung Park  ;  You Hyun Kang  ;  Hyun A Jin  ;  Joo Wan Kim  ;  Dong Hyuk Seo  ;  Dae Kyu Kim  ;  Tae Il Kim  ;  Won Ho Kim  ;  Seung Won Kim  ;  Jae Hee Cheon 
 American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol.315(1) : g128-g139, 2018 
Journal Title
 American Journal of Physiology - Gastrointestinal and Liver Physiology 
Issue Date
M2 macrophage ; guggulsterone ; inflammatory bowel disease ; interleukin-10 ; triggering receptor expressed on myeloid cells 1
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-kappaB, 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.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Seung Won(김승원) ORCID logo https://orcid.org/0000-0002-1692-1192
Kim, Won Ho(김원호) ORCID logo https://orcid.org/0000-0002-5682-9972
Kim, Tae Il(김태일) ORCID logo https://orcid.org/0000-0003-4807-890X
Park, Ki Cheong(박기청) ORCID logo https://orcid.org/0000-0002-3435-3985
Park, Soo Jung(박수정)
Cheon, Jae Hee(천재희) ORCID logo https://orcid.org/0000-0002-2282-8904
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