title: Small molecule tyrosine kinase inhibitors for the treatment of intestinal inflammation.
abstract: BACKGROUND
  We developed a series of dendritic cell autoimmune modulators (DCAMs) based on small molecule Flt3 receptor tyrosine kinase inhibitors (TKIs) for the inhibition of intestinal inflammation and oral delivery.
  
  
  METHODS
  DCAMs were administered orally during and after induction of dextran sodium sulfate (DSS)-induced colitis. Dendritic cell recruitment and inflammatory responses were determined in the mucosal immune system during acute intestinal inflammatory responses and mucosal recovery. Bone marrow-derived macrophages were utilized to define the mechanisms by which DCAMs can modify responses to microbial signals.
  
  
  RESULTS
  Oral doses of DCAMs prevented severe weight loss and mucosal inflammation associated with DSS colitis in mice. The presence of DCAMs increased the number of CD11c(+) PDCA1(+) dendritic cells, induced interleukin (IL)-10 expression, and reduced inflammatory cytokine expression in the mucosal immune system. Surprisingly, DCAMs regulated innate immune responses in macrophages resulting in the inhibition of tumor necrosis factor alpha (TNF-α) production and the induction of IL-10 expression during Toll-like receptor-mediated signaling.
  
  
  CONCLUSIONS
  We identified two new imidazoacridinone derivatives that protect mice from severe colitis and promote mucosal recovery by enhancing protective cytokine production while inhibiting proinflammatory stimuli during microbial recognition. These compounds are promising candidates for further development into potent orally available drugs for the prevention of colitis and promotion of mucosal recovery.
authors: Department of Medicine, Gastroenterology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors: Maninder
authors: M
authors: Sidhu
authors: Carmen Alonso
authors: CA
authors: Cotoner
authors: Bayasi
authors: B
authors: Guleng
authors: Seiji
authors: S
authors: Arihiro
authors: Sunyoung
authors: S
authors: Chang
authors: Kenneth W
authors: KW
authors: Duncan
authors: Alfred M
authors: AM
authors: Ajami
authors: Mydoanh
authors: M
authors: Chau
authors: Hans-Christian
authors: HC
authors: Reinecker
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000032:analysis; D003092:Colitis / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D016264:Dextran Sulfate / Q000633:toxicity; D005260:Female; D007113:Immunity, Innate / Q000187:drug effects; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D007422:Intestines / Q000187:drug effects* / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D015415:Biomarkers; D016207:Cytokines; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D016264:Dextran Sulfate; D011505:Protein-Tyrosine Kinases