title: FTY720 ameliorates oxazolone colitis in mice by directly affecting T helper type 2 functions.
abstract: The sphingosine-1-phosphate analogue FTY720 is known to alter migration and homing of lymphocytes via sphingosine-1-phosphate receptors. However, several studies indicate that its mode of action is more complex and that FTY720 may also directly influence cytokine effector functions. Therefore, we studied the effect of FTY720 in T helper type (Th2)-mediated oxazolone-induced colitis in mice. Following rectal oxazolone instillation, Th2 cells producing IL-13 induce a progressive colitis resembling human ulcerative colitis. A rectal enema of oxazolone [90 mg/kg body weight] was applied to BALB/c mice. FTY720 was administered i.p. from day 0 to 3 or from day 3 to 5 following the instillation of the haptenating agent. Assessment of severity of colitis was performed daily. FTY720 plasma levels were detected using LC-MS/MS-analysis. Colon tissue was analyzed macroscopically and microscopically, myeloperoxidase activity as well as cytokine levels of lamina propria CD4(+) T-cells and T1/ST2 expression were determined. Treatment with FTY720 prominently reduced the clinical and histopathologic severity of oxazolone-induced colitis, abrogating body weight loss, diarrhea, and macroscopic and microscopic intestinal inflammation. The therapeutic effects of FTY720 were associated with a prominent reduction of the key effector Th2 cytokines IL-13, IL-4 and IL-5. Strikingly, FTY720 inhibited GATA3 and T1/ST2 expression which represent highly relevant markers for Th2 differentiation and Th2 effector function, respectively. Our data provide the first evidence that FTY720 exhibits beneficial prophylactic as well as therapeutic effects in Th2-mediated experimental colitis by directly affecting Th2 cytokine profiles probably by reducing T1/ST2, thus offering a new auspicious therapeutic instrument for the treatment of human ulcerative colitis.
authors.affiliation: First Department of Internal Medicine, JWG University of Frankfurt am Main, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Daniel
authors.forename: Nico A
authors.initials: NA
authors.lastname: Sartory
authors.forename: Nadine
authors.initials: N
authors.lastname: Zahn
authors.forename: Ronald
authors.initials: R
authors.lastname: Schmidt
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.forename: Heinfried H
authors.initials: HH
authors.lastname: Radeke
authors.forename: Jurgen M
authors.initials: JM
authors.lastname: Stein
mesh_terms: D000276:Adjuvants, Immunologic / Q000009:adverse effects; D000818:Animals; D002478:Cells, Cultured; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010081:Oxazolone / Q000009:adverse effects; D011409:Propylene Glycols / Q000494:pharmacology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D010081:Oxazolone; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine