Over the previous 2 cycles we contributed to the evidence that TNFSF15/TL1A is a pro-inflammatory gene/protein with influence over severity and with a role in a severe clinical phenotype seen in animal models and humans. We have shown in humans that TNFSF15 haplotypes are associated with increased/sustained expression of TL1A and aggressive Crohn's disease. To determine the in vivo consequences of elevated TL1A, we generated Tl1a transgenic mice (Tl1a Tg) with sustained lymphoid and/or myeloid Tl1a expression. Tl1a Tg spontaneously developed mild inflammation in the duodenum and ileum, with enhanced collagen deposition in small bowel and colon;which under colitogenic conditions, fulminated into discontinuous ileal and duodenal small bowel inflammation and fibrostenosis, as well as worsened proximal colonic inflammation. Tl1a Tg colitic mice developed primary ureteral strictures and obliteration of small bile ducts reminiscent of human sclerosing cholangitis. Tl1a antibody reduced inflammation and reversed fibrosis. Tl1a modulates the adaptive immune response by increasing pro-inflammatory factors including Ifn?, Il13 and Il17. We generated mice with sustained lymphoid Tl1a expression but deficient in Ifn-?, Il13 or Il17a and showed that Ifn-? deficiency enhanced, while Il17a-deficiency reduced inflammation and fibrosis, suggesting that Tl1a synergizes with other factors to modulate inflammation and fibrosis. To determine whether Tl1a can directly signal intestinal fibroblasts, we generated Dr3 deficient (Dr3-/-) mice and showed that Dr3, the only known receptor for Tl1a, is expressed on wild type (WT), but not Dr3-/- intestinal fibroblasts. Tl1a can increase collagen expression on WT but not Dr3-/- intestinal fibroblasts. Results from preliminary human studies are consistent with our findings in mice that TL1A modulates the severity and location of intestinal inflammation and fibrosis. CD patients with elevated TL1A expression require smaller bowel surgeries, have primary ureteral strictures, and have relative rectal sparing of inflammation. As seen in the mouse, our in vitro studies demonstrated direct TL1A induction of collagen expression from isolated human mucosal fibroblasts. Based on the work from our prior grant cycle and particularly the data supporting a role for TL1A in fibrosis leading to complicated clinical phenotypes in murine models and defined patient populations, we hypothesize that: TNFSF15/TL1A plays a central role in the induction and amplification of fibrosis by: 1) direct induction of fibroblast activation and differentiation into to myofibroblasts, which then express fibrosis-related factors;and 2) indirect induction of inflammatory cytokine programs, which independently activate fibrosis.

Public Health Relevance

Inflammatory bowel diseases (IBD) affect more than 1,000,000 Americans. The studies of the role of tumor necrosis factor superfamily member (TNFSF)15/tumor necrosis factor-like cytokine (TL)1A (TNFSF15/TL1A) in fibrogenesis and severity of inflammation will help to define pathogenesis and identify potential therapeutic targets for the most severely and significantly affected by this illness.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01DK056328-16
Application #
8691159
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Hamilton, Frank A
Project Start
Project End
Budget Start
Budget End
Support Year
16
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
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
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
Shih, David Q; Barrett, Robert; Zhang, Xiaolan et al. (2011) Constitutive TL1A (TNFSF15) expression on lymphoid or myeloid cells leads to mild intestinal inflammation and fibrosis. PLoS One 6:e16090
Muller, Marioly; Cardenas, Cesar; Mei, Lijuan et al. (2011) Constitutive cAMP response element binding protein (CREB) activation by Alzheimer's disease presenilin-driven inositol trisphosphate receptor (InsP3R) Ca2+ signaling. Proc Natl Acad Sci U S A 108:13293-8
Shih, David Q; Michelsen, Kathrin S; Barrett, Robert J et al. (2011) Insights into TL1A and IBD pathogenesis. Adv Exp Med Biol 691:279-88
Nguyen, Minh; Bradford, Kara; Zhang, Xiaolan et al. (2011) Cytomegalovirus Reactivation in Ulcerative Colitis Patients. Ulcers 2011:
Cardenas, Cesar; Miller, Russell A; Smith, Ian et al. (2010) Essential regulation of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to mitochondria. Cell 142:270-83
Eckenrode, Emily F; Yang, Jun; Velmurugan, Gopal V et al. (2010) Apoptosis protection by Mcl-1 and Bcl-2 modulation of inositol 1,4,5-trisphosphate receptor-dependent Ca2+ signaling. J Biol Chem 285:13678-84

Showing the most recent 10 out of 29 publications