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BACKGROUND & AIMS: Induction of colitis in mice by administration of oxazolone is mediated by T-helper (Th) 2 cells and has features of human ulcerative colitis. We investigated whether activation of interleukin (IL)-4Rα on T and B cells determines their effector functions and mediates oxazolone-induced colitis. METHODS: We studied induction of colitis with oxazolone in wild-type mice and those with CD4⁺ T cells that did not express IL-4Rα (Lck^creIL-4Rα^-/lox). We also generated mice with B cells that did not express IL-4Rα (mb1^creIL-4Rα^-/lox) and studied induction of colitis. RESULTS: Lck^creIL-4Rα^-/lox mice did not develop colitis in response to oxazolone, and their levels of IL-4, IL-13, and immunoglobulin (Ig) E were reduced. Adoptive transfer of naïve, wild-type CD4⁺ Th cells depleted of natural killer T cells to Lck^creIL-4Rα^-/lox mice restored their susceptibility to colitis. In contrast, Lck^creIL-4Rα^-/lox mice maintained their protection against colitis when IL-13-deficient CD4⁺ T cells were transferred. These findings indicate that development of colitis involves not only natural killer T-cell functions, but also requires IL-13 production by CD4⁺ T helper cells. Mb1^creIL-4Rα^-/lox mice, which cannot produce IgE, were also protected against oxazolone-induced colitis. Blocking IgE binding significantly reduced mast cell numbers in colons and protected wild-type BALB/c mice from the onset of colitis. CONCLUSIONS: IL-4 appears to induce CD4⁺ Th2 cells to produce IL-13 and B cells to produce IgE, which together mediate oxazolone-induced colitis in mice.