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lüll Toll-like receptor-7 ligand Imiquimod induces type I interferon and antimicrobial peptides to ameliorate dextran sodium sulfate-induced acute colitis Sainathan SK; Bishnupuri KS; Aden K; Luo Q; Houchen CW; Anant S; Dieckgraefe BKInflamm Bowel Dis 2012[May]; 18 (5): 955-67BACKGROUND: 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 mug/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.|Administration, Oral[MESH]|Administration, Topical[MESH]|Aminoquinolines/*therapeutic use[MESH]|Animals[MESH]|Antimicrobial Cationic Peptides/*metabolism[MESH]|Biomarkers/metabolism[MESH]|Colitis/chemically induced/metabolism/*prevention & control[MESH]|Cytokines/metabolism[MESH]|Dextran Sulfate/*toxicity[MESH]|Female[MESH]|Gastrointestinal Tract/drug effects/metabolism/microbiology[MESH]|Gene Expression Profiling[MESH]|Humans[MESH]|Imiquimod[MESH]|Interferon Inducers/*therapeutic use[MESH]|Interferon Type I/*metabolism[MESH]|Mice[MESH]|Mice, Inbred BALB C[MESH]|Oligonucleotide Array Sequence Analysis[MESH]|Peroxidase/metabolism[MESH]|RNA, Messenger/genetics[MESH]|Real-Time Polymerase Chain Reaction[MESH]|Salmonella Infections/microbiology/mortality/prevention & control[MESH]|Salmonella typhimurium[MESH]|Survival Rate[MESH]|Toll-Like Receptor 7/*metabolism[MESH] |