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

Satheesh K. Sainathan, Kumar S. Bishnupuri, Konrad Aden, Qizhi Luo, Courtney W. Houchen, Shrikant Anant, Brian K. Dieckgraefe

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

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.

Original languageEnglish
Pages (from-to)955-967
Number of pages13
JournalInflammatory bowel diseases
Volume18
Issue number5
DOIs
StatePublished - May 2012

Keywords

  • Epithelial cells
  • Inflammatory bowel diseases
  • Innate immunity
  • Mucosa

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