Crohn's disease is a chronic inflammatory disease of the gastrointestinal tract characterized by an imbalanced TH1 response. IFN-gamma, TNF, and three members of the TNF superfamily (CD40, OX40 and LIGHT) are known to be key factors in the development or regulation of mucosal inflammation in rodents. Production of both TNF and IFN-gamma is exaggerated in the mucosa of patients with Crohn's disease. The effectiveness of agents that bind TNF for the treatment of Crohn's disease is evidence that TNF has an important role in Crohn's disease mucosal inflammation. A very recent pilot study using blocking antibodies to IFN-gamma suggested a dose-dependent, attenuation of disease activity in Crohn's disease patients, implying a major role for mucosal IFN-gamma in disease initiation and severity. Our studies on potentiation of IFN-gamma, production by TNF provided evidence for the existence of a soluble factor(s), produced by LPMC, which augmented IFN-gamma production by activated T-cells, acting independently of IL-12 and IL-18, as well as in synergy with them. The TNF-like molecule (TL1A) is a strong candidate for this factor. TL1A has a predicted N-terminal transmembrane domain and binds the TNF-family receptor, DR3, for which no other ligand had been identified. TL1A augments activation-induced IFN-gamma production, in both PB and LP T-cells, independently of, yet in synergy with IL-12 and IL-18. In contrast to resting PB T-cells, small fractions of T-cells from control and ulcerative colitis mucosa stain for membrane -TL1A and for DR3. In contrast, markedly larger fractions of LP CD4+ T-cells from active Crohn's disease lesions are membrane TL1A (mbTL1A) and DR3 positive. In addition, TL1A mRNA in active lesions of Crohn's disease mucosa is elevated several-fold above normal. Furthermore, only in cells from Crohn's disease lesions is IFN-? production by stimulated LP T-cells partially inhibited by anti-TL1A monoclonal antibody. These data suggest that this TNF-family cytokine plays an important role in increasing the level of IFN-? in Crohn's disease mucosa. Our overall hypothesis is that TL1A and its receptor DR3 act to increase the severity of Crohn's disease pathology by potentiating IFN-? production by LP CD4 T-cells, independently of, or in conjunction with IL-12 and IL-18. We will begin address this hypothesis by 1) determining the cellular events involved in augmentation of IFN-? protein production by TL1A and/or IL-12 and IL-18; 2) determining the molecular events that lead to augmentation of IFN-gamma mRNA expression by TL1A and/or IL-12 and IL-18; and 3) identifying the cellular and molecular mechanisms responsible for increased TL1A expression in Crohn's disease mucosa.
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