The requirements for
interleukin (
IL)-12/signal transducer and activator of transcription (Stat)-4 signaling and induction of T cell-specific
interferon (IFN)-gamma expression in the development of T helper cell (Th)1-type pathology were examined in two different models of experimental
colitis. In each model, abnormal reconstitution of the T cell compartment in immunodeficient mice by adoptive cell transfer leads to a
wasting syndrome and
inflammation of the colon, induced by IFN-gamma and
tumor necrosis factor (
TNF)-alpha-producing T cells. We show here that treatment with anti-IL-12
antibodies in one of the models, or reconstitution with T cells from Stat-4-deficient (Stat-4(null)) mice in both models resulted in a milder disease in the majority of recipient animals, compared with those that were left untreated or that had been reconstituted with wt cells. Protected mice in each group also harbored lower frequencies of IFN-gamma-producing T cells than did diseased mice, suggesting that effects on wasting and
colitis resulted from the attenuation of IFN-gamma expression by T cells. To test whether the development of pathogenic T cells in the two
colitis models was directly dependent on T cell-specific IFN-gamma expression, IFN-gammanull donors were used for T cell reconstitution in each system. Surprisingly, large numbers of IFN-gammanull-reconstituted mice developed wasting and
colitis, which in many cases was of comparable severity to that seen in animals reconstituted with wt cells. Furthermore, T cells from these animals expressed
TNF-alpha, demonstrating that they had retained the ability to produce another proinflammatory
cytokine. Taken together, these results demonstrate that in some forms of chronic experimental
colitis the development of pathogenic T cells is influenced predominantly, though not exclusively, by
IL-12 via the actions of Stat-4
proteins. Furthermore, our data suggest that in the models of
colitis studied here the effects of
IL-12/Stat-4 or other Th1 promoting pathways are not limited to the induction of IFN-gamma gene expression in T lymphocytes.