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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK056328-09
Application #
7270399
Study Section
Special Emphasis Panel (ZRG1-ALTX-4 (02))
Program Officer
Hamilton, Frank A
Project Start
1999-08-15
Project End
2009-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
9
Fiscal Year
2007
Total Cost
$369,790
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
Jacob, Noam; Jacobs, Jonathan P; Kumagai, Kotaro et al. (2018) Inflammation-independent TL1A-mediated intestinal fibrosis is dependent on the gut microbiome. Mucosal Immunol 11:1466-1476
Zhang, Hong; Zheng, Libo; McGovern, Dermot P B et al. (2017) Myeloid ATG16L1 Facilitates Host-Bacteria Interactions in Maintaining Intestinal Homeostasis. J Immunol 198:2133-2146
Sidhu-Varma, Maninder; Shih, David Q; Targan, Stephan R (2016) Differential Levels of Tl1a Affect the Expansion and Function of Regulatory T Cells in Modulating Murine Colitis. Inflamm Bowel Dis 22:548-59
Khanna, Puja Vora; Shih, David Quan; Haritunians, Talin et al. (2014) Use of animal models in elucidating disease pathogenesis in IBD. Semin Immunopathol 36:541-51
Shih, D Q; Zheng, L; Zhang, X et al. (2014) Inhibition of a novel fibrogenic factor Tl1a reverses established colonic fibrosis. Mucosal Immunol 7:1492-503
Zheng, Libo; Zhang, Xiaolan; Chen, Jeremy et al. (2013) SUSTAINED TL1A (TNFSF15) EXPRESSION ON BOTH LYMPHOID AND MYELOID CELLS LEADS TO MILD SPONTANEOUS INTESTINAL INFLAMMATION AND FIBROSIS. Eur J Microbiol Immunol (Bp) 3:11-20
Gonsky, Rivkah; Deem, Richard L; Targan, Stephan R (2013) Multiple activating and repressive cis-promoter regions regulate TNFSF15 expression in human primary mononuclear cells. Cytokine 63:36-42
Vora, Puja; Shih, David Quan; McGovern, Dermot Patrick et al. (2012) Current concepts on the immunopathogenesis of inflammatory bowel disease. Front Biosci (Elite Ed) 4:1451-77
Barrett, Robert; Zhang, Xiaolan; Koon, Hon Wai et al. (2012) Constitutive TL1A expression under colitogenic conditions modulates the severity and location of gut mucosal inflammation and induces fibrostenosis. Am J Pathol 180:636-49
Cardenas, Cesar; Foskett, J Kevin (2012) Mitochondrial Ca(2+) signals in autophagy. Cell Calcium 52:44-51

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