title: 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.
authors.affiliation: Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Satheesh K
authors.initials: SK
authors.lastname: Sainathan
authors.forename: Kumar S
authors.initials: KS
authors.lastname: Bishnupuri
authors.forename: Konrad
authors.initials: K
authors.lastname: Aden
authors.forename: Qizhi
authors.initials: Q
authors.lastname: Luo
authors.forename: Courtney W
authors.initials: CW
authors.lastname: Houchen
authors.forename: Shrikant
authors.initials: S
authors.lastname: Anant
authors.forename: Brian K
authors.initials: BK
authors.lastname: Dieckgraefe
mesh_terms: D000284:Administration, Oral; D000287:Administration, Topical; D000634:Aminoquinolines / Q000627:therapeutic use*; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity*; D005260:Female; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D020869:Gene Expression Profiling; D006801:Humans; D000077271:Imiquimod; D007369:Interferon Inducers / Q000627:therapeutic use*; D007370:Interferon Type I / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D020411:Oligonucleotide Array Sequence Analysis; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012480:Salmonella Infections / Q000382:microbiology / Q000401:mortality / Q000517:prevention & control; D012486:Salmonella typhimurium; D015996:Survival Rate; D051199:Toll-Like Receptor 7 / Q000378:metabolism*
chemical_list: D000634:Aminoquinolines; D023181:Antimicrobial Cationic Peptides; D015415:Biomarkers; D016207:Cytokines; D007369:Interferon Inducers; D007370:Interferon Type I; D012333:RNA, Messenger; D051199:Toll-Like Receptor 7; D016264:Dextran Sulfate; D009195:Peroxidase; D000077271:Imiquimod