Dataset Information

Toll-like receptor-7 ligand Imiquimod induces type I interferon and antimicrobial peptides to ameliorate dextran sodium sulfate-induced acute colitis.

ABSTRACT:

Background

The pathogenesis of inflammatory bowel disease (IBD) is associated with a dysregulated mucosal immune response. Certain stimulators of innate immunity (CpG DNA or GM-CSF) are reported to be anti-inflammatory in IBD. Toll-like receptor-7 (TLR7) is an important regulator of innate immunity and its activation plays a key role in induction of type I interferon (IFN). The present study tests the hypothesis that the TLR7 agonists Imiquimod has therapeutic efficacy in IBD.

Methods

Acute colitis was induced in Balb/c mice by giving 5% dextran sodium sulfate (DSS) in drinking water for 7 days. Mice were treated with Imiquimod either orally or topically and its therapeutic effects on disease activity were examined. Isolated mouse CD11c+ dendritic cells and human intestinal epithelial cells (HT29, HCT116) were treated with Imiquimod (10 μg/mL) and their susceptibility to intracellular Salmonella typhimurium infection was assessed by gentamicin protection assay.

Results

Oral administration of Imiquimod induced type I IFN expression in the gastrointestinal mucosa and ameliorated DSS-induced acute colitis as assessed by clinical parameters, histology, and mRNA expression of proinflammatory cytokines. Topical administration of Imiquimod also ameliorated DSS colitis by inducing the expression of type I IFN in the colonic mucosa. However, no evidence for a systemic IFN response was observed. Imiquimod treatments to both CD11c+ and intestinal epithelial cells significantly increased expression of antimicrobial peptides (AMPs) and reduced survival of intracellular S. typhimurium.

Conclusions

Imiquimod induces type I IFN and AMP to ameliorate DSS-induced acute colitis and prevents Salmonella survival. Therefore, Imiquimod treatments provide a new therapeutic approach for IBD patients.

SUBMITTER: Sainathan SK

PROVIDER: S-EPMC3878618 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Toll-like receptor-7 ligand Imiquimod induces type I interferon and antimicrobial peptides to ameliorate dextran sodium sulfate-induced acute colitis.

Sainathan Satheesh K SK Bishnupuri Kumar S KS Aden Konrad K Luo Qizhi Q Houchen Courtney W CW Anant Shrikant S Dieckgraefe Brian K BK

Inflammatory bowel diseases 20110926 5

<h4>Background</h4>The pathogenesis of inflammatory bowel disease (IBD) is associated with a dysregulated mucosal immune response. Certain stimulators of innate immunity (CpG DNA or GM-CSF) are reported to be anti-inflammatory in IBD. Toll-like receptor-7 (TLR7) is an important regulator of innate immunity and its activation plays a key role in induction of type I interferon (IFN). The present study tests the hypothesis that the TLR7 agonists Imiquimod has therapeutic efficacy in IBD.<h4>Methods ...[more]

PMID: 21953855

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Project description:This study aimed to investigate the ameliorative effect of the polysaccharides of Panax quinquefolius (WQP) on ulcerative colitis (UC) induced by dextran sulfate sodium (DSS) in mice and to explore its mechanism. Male C57BL/6J mice were randomly divided into the control group (C), model group (DSS), positive control mesalazine (100 mg/kg, Y) group, and low (50 mg/kg, L), medium (100 mg/kg, M) and high dose (200 mg/kg, H) of WQP groups. The UC model was induced by free drinking water with 2.5% DSS for 7 days. During the experiment, the general condition of the mice was observed, and the disease activity index (DAI) was scored. The conventional HE staining was used to observe pathological changes in mice's colon, and the ELISA method was used to detect the levels of interleukin-6 (IL-6), IL-4, IL-8, IL-10, IL-1β and tumor necrosis factor-α (TNF-α) in mice's colon. The changes in gut microbiota in mice were detected by high-throughput sequencing; the concentration of short-chain fatty acids (SCFAs) was determined by gas chromatography; the expression of related proteins was detected by Western blot. Compared with the DSS group, the WQP group showed a significantly lower DAI score of mice and an alleviated colon tissue injury. In the middle- and high-dose polysaccharides groups, the levels of pro-inflammatory cytokines IL-6, IL-8, IL-1β and TNF-α in the colonic tissue were significantly decreased (P<0.05), while the levels of IL-4 and IL-10 were significantly increased (P<0.05). The 16S rRNA gene sequencing results showed that different doses of WQP could regulate the composition and diversity of gut microbiota and improve its structure. Specifically, at the phylum level, group H showed an increased relative abundance of Bacteroidetes and a decreased relative abundance of Firmicutes compared with the DSS group, which was closer to the case in group C. At the family level, the relative abundance of Rikenellaceae in L, M and H groups increased significantly, close to that in group C. At the genus level, the relative abundance of Bacteroides, Shigella and Oscillospira in the H group increased significantly, while that of Lactobacillus and Prevotella decreased significantly. The high-dose WQP group could significantly increase the contents of acetic acid, propionic acid, butyric acid, and total SCFAs. Different doses of WQP also increased the expression levels of tight junction proteins ZO-1, Occludin and Claudin-1. To sum up, WQP can regulate the gut microbiota structure of UC mice, accelerate the recovery of gut microbiota, and increase the content of Faecal SCFAs and the expression level of tight junction proteins in UC mice. This study can provide new ideas for the treatment and prevention of UC and theoretical references for the application of WQP.

Dataset Information

Toll-like receptor-7 ligand Imiquimod induces type I interferon and antimicrobial peptides to ameliorate dextran sodium sulfate-induced acute colitis.

Background

Methods

Results

Conclusions

Publications

Toll-like receptor-7 ligand Imiquimod induces type I interferon and antimicrobial peptides to ameliorate dextran sodium sulfate-induced acute colitis.

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