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The Effects and Mechanisms of Lipopolysaccharide in Dextran Sulphate Sodium Induced Inflammatory Bowel Disease

Author: LanYan
Tutor: XiangMing
School: Huazhong University of Science and Technology
Course: Pharmacology
Keywords: Inflammatory bowel disease Lipopolysaccharide Dextran sulfatesodium Dendritic cell Toll-like receptor4 immune tolerance
CLC: R96
Type: Master's thesis
Year: 2012
Downloads: 2
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Abstract

Background: Inflammatory bowel disease (IBD), encompassing the chronicrelapsing inflammatory disorders, Crohn’s disease and ulcerative colitis, is a kind ofnonspecific inflammatory disease which etiology and pathogenesis are not completelyclear. In recent years, the morbidity and mortality of the IBD is rising year by year allof the world，and the disease has complex pathological changes and multifariousclinical symptom, if we don’t timely ease and cure, it will possibly lead theoccurrence of cancer. Hence, it is considered as one of the modern refractory diseasesby the World Health Organization.The pathogenesis of IBD involves environment, genetics, intestinal flora and theimmune response,but none of these components can alone explain IBD, it is theirintegration and reciprocal, and the immunological factor is considered to be one of themost important factors. Toll-like receptor4(TLR4) is an important pattern-recognitionreceptor(PRR)and plays a crucial role in innate immunity; It is also a bridge whichconnects innate immunity and acquired immunity. Therefore, it is known as the gateof the inflammatory response. For the past few years, the role of TLR4signalingpathways has been widely studied in the IBD patients, which excessively activatedwould lead to abnormal immune responses, and then result in continuous expandinginflammatory reaction.Lipopolysaccharide(LPS), one of the important ligands of the TLR4, is a gramnegative bacteria and a proinflammatory factor. When it combines with TLR4, it willactivate a series of TLR4signaling pathways, and then lead to the natural immuneresponse and inflammatoty reaction. However, recent studies have shown that LPShas ameliorated dextran sodium sulfate(DSS)-induced colitis, possibly through TLR4down-regulation, but the specific mechanism is still unclear. Objective: To explore effects and the molecular mechanisms of the different doses ofLPS on the development of DSS-induced colitis.Methods:(1) Balb/c mice were intraperitoneal administration10μg of LPS on days1and8, and then were given3%DSS dissovled in the drinking water for7days. Theincidence and severity of DSS-induced colitis and histopathology of inflammationwere evaluated.(2) DCs were isolated from bone marrow and were cultured in RPMI-1640culturemedium supplemented with recombinant GM-CSF and IL-4. Then the CD86, MHC-Ⅱphenotypes of DCs were tested by FACS. The molecular mechanisms of LPS of therelated protein and genes on the TLR4signaling pathways were examined by theWestern blot and Polymerase Chain Reaction(PCR) analysis.Results:(1) Intraperitoneal administration with a single dose of LPS for DSS-inducedcolitis in mice demonstrated significantly attenuated the severity and inflammation ofthe colitis as assessed by DAI scoring and histopahthologic analysis compared withthe control group and multiple doses of LPS group.(2) FACS result revealed that the costimulatory molecules of CD86, MHC-Ⅱexpressed on DCs were obviously lower after the single dose of LPS treated,compared with the control group and multiple doses of LPS group; The TLR4andNF-κB expression was significantly down-regulated in the single dose of LPScompared with the control group and multiple doses of LPS group. In addition, themRNA expression of the related genes in TLR4signaling pathways are alsosignificantly lower in the single dose of LPS than the control group and multipledoses of LPS group.Conclusion: These results suggest the attenuated inflammation was associated withthe down-regulation of TLR4and elicited immune tolerance, it would help to understand the pathogenesis of IBD and be a valuable candidate for the treatment ofIBD.

The Effects and Mechanisms of Lipopolysaccharide in Dextran Sulphate Sodium Induced Inflammatory Bowel Disease

Abstract

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