Protective Role of the Toll-Like Receptor 5 Agonist KMRC011 against Murine Colitis Induced by Citrobacter rodentium and Dextran Sulfate Sodium
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This study aimed to identify the therapeutic ability of a novel toll-like receptor (TLR) 5 agonist, KMRC011, on ulcerative colitis induced by Citrobacter rodentium and dextran sulfate sodium in a C57BL/6N mouse model. Ulcerative colitis was induced in the mice by the oral administration of 1% dextran sulfate sodium in sterile drinking water for seven days ad libitum, followed by C. rodentium infection on the seventh day by intra-gastric administration (DSS-CT group). KMRC011 was administered intramuscularly at both 24 h and 15 min before (Treatment 1 group), and at both 15 min and 24 h after (Treatment 2 group) the C. rodentium infection. The length of the large intestine and histopathological counts were significantly greater and mucosal thickness was significantly thinner in the Treatment 1 group compared to the DSS-CT and Treatment 2 groups. Il-6 and Il-10 mRNA expression levels were upregulated, while Ifn-γ and Tnf-α mRNA expression levels were significantly downregulated in the Treatment 1 group, compared to the DSS-CT group. NF-κB p65 expression level was elevated due to ulcerative colitis in the DSS-CT group, but was significantly downregulated in the Treatment 1 group. Overall, KMRC011 showed protective effects against murine colitis by inhibiting NF-κB signaling.
Abstract
This study aimed to identify the therapeutic ability of a novel toll-like receptor (TLR) 5 agonist, KMRC011, on ulcerative colitis induced by Citrobacter rodentium and dextran sulfate sodium in a C57BL/6N mouse model. Ulcerative colitis was induced in the mice by the oral administration of 1% dextran sulfate sodium in sterile drinking water for seven days ad libitum, followed by C. rodentium infection on the seventh day by intra-gastric administration (DSS-CT group). KMRC011 was administered intramuscularly at both 24 h and 15 min before (Treatment 1 group), and at both 15 min and 24 h after (Treatment 2 group) the C. rodentium infection. The length of the large intestine and histopathological counts were significantly greater and mucosal thickness was significantly thinner in the Treatment 1 group compared to the DSS-CT and Treatment 2 groups. Il-6 and Il-10 mRNA expression levels were upregulated, while Ifn-γ and Tnf-α mRNA expression levels were significantly downregulated in the Treatment 1 group, compared to the DSS-CT group. NF-κB p65 expression level was elevated due to ulcerative colitis in the DSS-CT group, but was significantly downregulated in the Treatment 1 group. Overall, KMRC011 showed protective effects against murine colitis by inhibiting NF-κB signaling.
참고문헌 (36)
- Schirmer M, "Microbial genes and pathways in inflammatory bowel disease", Nat. Rev. Microbiol, 17, pp.497~511 (2019)
- Cucchiara S, "Interactions between intestinal microbiota and innate immune system in pediatric inflammatory bowel disease", J. Clin. Gastroenterol, 46, pp.S64~S66 (2012)
- Bauer C, "Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome", Gut, 59, pp.1192~1199 (2010)
- Shanahan F, "Inflammatory bowel disease: immunodiagnostics, immunotherapeutics, and ecotherapeutics", Gastroenterology, 120, pp.622~635 (2001)
- Levin A, "Toll-like receptors in inflammatory bowel disease-stepping into uncharted territory", World J. Gastroenterol, 14, pp.5149~5153 (2008)
- Neurath M, "TNBS-colitis", Int. Rev. Immunol, 19, pp.51~62 (2000)
- Wirtz S, "Mouse models of inflammatory bowel disease", Adv. Drug Deliv. Rev, 59, pp.1073~1083 (2007)
- Perse M, "Dextran sodium sulphate colitis mouse model: traps and tricks", J. Biomed. Biotechnol, 2012, pp.718617~ (2012)
- Wirtz S, "Chemically induced mouse models of intestinal inflammation", Nat. Protoc, 2, pp.541~546 (2007)
- Okayasu I, "A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice", Gastroenterology, 98, pp.694~702 (1990)
- Chassaing B, "Dextran sulfate sodium (DSS)-induced colitis in mice", Curr. Protoc. Immunol, 104, pp.Unit–15.25~ (2014)
- Alipour M, "A balanced IL-1beta activity is required for host response to Citrobacter rodentium infection", PLoS One, 8, pp.e80656~ (2013)
- Luperchio SA, "Molecular pathogenesis of Citrobacter rodentium and transmissible murine colonic hyperplasia", Microbes Infect, 3, pp.333~340 (2001)
- Schauer DB, "Genetic and biochemical characterization of Citrobacter rodentium sp", J. Clin. Microbiol, 33, pp.2064~2068 (1995)
- Deng W, "Locus of enterocyte effacement from Citrobacter rodentium: sequence analysis and evidence for horizontal transfer among attaching and effacing pathogens", Infect. Immun, 69, pp.6323~6335 (2001)
- Mundy R, "Citrobacter rodentium of mice and man", Cell Microbiol, 7, pp.1697~1706 (2005)
- Song WS, "TLR5 binding and activation by KMRC011, a flagellin-derived radiation countermeasure", Biochem. Biophys. Res. Commun, 508, pp.570~575 (2019)
- Xavier RJ, "Unravelling the pathogenesis of inflammatory bowel disease", Nature, 448, pp.427~434 (2007)
- Kim JY, "Radioprotective effect of newly synthesized toll-like receptor 5agonist, KMRC011, in mice exposed to total-body irradiation", J. Radiat. Res, 60, pp.432~441 (2019)
- Xu Y, "CBLB502 administration protects gut mucosal tissue in ulcerative colitis by inhibiting inflammation", Ann. Transl. Med, 4, pp.301~ (2016)
- 박진일, "A murine colitis model developed using a combination of dextran sulfate sodium and Citrobacter rodentium", The Journal of Microbiology, 56(4), pp.272~279 (2018), 한국미생물학회[DOI]
- Singh K, "The apolipoprotein E-mimetic peptide COG112inhibits NF-kappaB signaling, proinflammatory cytokine expression, and disease activity in murine models of colitis", J. Biol. Chem, 286, pp.3839~3850 (2001)
- Kitajima S, "Histological analysis of murine colitis induced by dextran sulfate sodium of different molecular weights", Exp. Anim, 49, pp.9~15 (2000)
- Hibi T, "Interleukin 2 and interferon-gamma augment anticolon antibody dependent cellular cytotoxicity in ulcerative colitis", Gut, 34, pp.788~793 (1993)
- Raab Y, "Neutrophil mucosal involvement is accompanied by enhanced local production of interleukin-8 in ulcerative-colitis", Gut, 34, pp.1203~1206 (1993)
- Yu D, "Regulation of proinflammatory cytokine expression in primary mouse astrocytes by coronavirus infection", J. Virol, 83, pp.12204~12214 (2009)
- Moore KW, "Interleukin-10 and the interleukin-10 receptor", Annu. Rev. Immunol, 19, pp.683~765 (2001)
- Heller F, "Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution", Gastroenterology, 129, pp.550~564 (2005)
- Zhang H, "Interleukin 6 inhibition by triptolide prevents inflammation in a mouse model of ulcerative colitis", Exp. Ther. Med, 14, pp.2271~2276 (2017)
- Reinisch W, "Clinical relevance of serum interleukin-6 in Crohn’s disease: single point measurements, therapy monitoring, and prediction of clinical relapse", Am. J. Gastroenterol, 94, pp.2156~2164 (1999)
- Scheller J, "The pro- and anti-inflammatory properties of the cytokine interleukin-6", Biochim. Biophys. Acta, 1813, pp.878~888 (2011)
- Schreiber S, "Activation of nuclear factor kappa B in inflammatory bowel disease", Gut, 42, pp.477~484 (1998)
- Andresen L, "Activation of nuclear factor kappaB in colonic mucosa from patients with collagenous and ulcerative colitis", Gut, 54, pp.503~509 (2005)
- Assas BM, "Anti‐inflammatory effects of infliximab in mice are independent of tumour necrosis factor α neutralization", Clin. Exp. Immunol, 187, pp.225~233 (2017)
- Guidi L, "Increased levels of NF-κB inhibitors (IκBα and IκBγ) in the intestinal mucosa of crohn's disease patients during infliximab treatment", Int. J. Immunopathol. Pharmacol, 18, pp.155~164 (2005)
- Dou W, "Protective effect of naringenin against experimental colitis via suppression of Toll-like receptor 4", NF-kappaB signalling, 2013, pp.110, 599~608