title: Preventive and therapeutic effects of tacrolimus in an interleukin-10-deficient mouse model of colitis.
abstract: OBJECTIVE
  To investigate the preventive and therapeutic effects of tacrolimus on colonic inflammation in interleukin-10-deficient (IL-10(-/-)) mice, which spontaneously develop T-cell-mediated colitis.
  
  
  METHODS
  Tacrolimus or prednisolone, an anti-inflammatory glucocorticoid, was administered to IL-10(-/-) mice with pre- or post-symptomatic colitis. Effects on colonic inflammation were examined by measuring indices of colitis such as colonic weight/length ratio, cell infiltration, and goblet cell depletion. Effects on cytokine production in colonic lamina propria mononuclear cells (LPMCs) isolated from IL-10(-/-) mice were also examined.
  
  
  RESULTS
  Tacrolimus prevented development of colitis and improved already-developed colitis. Prednisolone prevented the development of colitis, but had no effect on already-developed colitis. Tacrolimus completely inhibited IFN-γ and TNF-α production of activated T-cells in LPMCs, but only partially inhibited IFN-γ, TNF-α, and IL-12 production of activated monocytes/macrophages in LPMCs. Prednisolone inhibited cytokine production in both cell types but exhibited greater potency on monocytes/macrophages than on T-cells.
  
  
  CONCLUSIONS
  These results suggest that the preventive and therapeutic effect of tacrolimus in IL-10(-/-) mice colitis might be attributed to the inhibition of colonic T-cell activation rather than monocyte/macrophage activation. T-cell immunosuppression may thus be a promising strategy for treating colonic inflammation.
authors.affiliation: Applied Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma, 21, Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan. yohei.okada@jp.astellas.com
authors.forename: Yohei
authors.initials: Y
authors.lastname: Okada
authors.forename: Noriaki
authors.initials: N
authors.lastname: Maeda
authors.forename: Shoji
authors.initials: S
authors.lastname: Takakura
authors.forename: Keiji
authors.initials: K
authors.lastname: Miyata
authors.forename: Masahiro
authors.initials: M
authors.lastname: Koshiba
mesh_terms: D000818:Animals; D003092:Colitis / Q000235:genetics*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007249:Inflammation; D016753:Interleukin-10 / Q000235:genetics*; D008264:Macrophages / Q000166:cytology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000166:cytology; D010641:Phenotype; D011239:Prednisolone / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D016559:Tacrolimus / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D011239:Prednisolone; D016559:Tacrolimus