Toll-like receptor-7 ligand imiquimod induces type I interferon and antimicrobial peptides to ameliorate dextran sodium sulfate-induced acute colitis
Satheesh K. Sainathan PhD
Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA
Search for more papers by this authorKumar S. Bishnupuri PhD
Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA
Search for more papers by this authorKonrad Aden MD
Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, Germany
Search for more papers by this authorQizhi Luo MD
Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA
Search for more papers by this authorCourtney W. Houchen MD
University of Oklahoma, Health Science Center, Oklahoma, USA
Search for more papers by this authorShrikant Anant PhD
Kansas University, School of Medicine, Kansas City, Kansas, USA
Search for more papers by this authorCorresponding Author
Brian K. Dieckgraefe MD, PhD
Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA
Associate Professor, Washington University School of Medicine, 4940 Parkview Place, Campus Box 8124, St.Louis, MO 63110Search for more papers by this authorSatheesh K. Sainathan PhD
Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA
Search for more papers by this authorKumar S. Bishnupuri PhD
Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA
Search for more papers by this authorKonrad Aden MD
Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, Germany
Search for more papers by this authorQizhi Luo MD
Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA
Search for more papers by this authorCourtney W. Houchen MD
University of Oklahoma, Health Science Center, Oklahoma, USA
Search for more papers by this authorShrikant Anant PhD
Kansas University, School of Medicine, Kansas City, Kansas, USA
Search for more papers by this authorCorresponding Author
Brian K. Dieckgraefe MD, PhD
Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA
Associate Professor, Washington University School of Medicine, 4940 Parkview Place, Campus Box 8124, St.Louis, MO 63110Search for more papers by this authorAbstract
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. (Inflamm Bowel Dis 2011;)
Supporting Information
Additional Supporting Information may be found in the online version of this article.
| Filename | Description |
|---|---|
| IBD_21867_sm_SuppFig1.tif234.4 KB | Supporting Information Figure 1 |
| IBD_21867_sm_SuppFig2.tif2.3 MB | Supporting Information Figure 2 |
| IBD_21867_sm_SuppTabI.doc44.5 KB | Supporting Information Table 1 |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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