title: Constitutive TL1A expression under colitogenic conditions modulates the severity and location of gut mucosal inflammation and induces fibrostenosis.
abstract: Intestinal fibrostenosis is a hallmark of severe Crohn's disease and can lead to multiple surgeries. Patients with certain TNFSF15 variants overexpress TL1A. The aim of this study was to determine the effect of TL1A overexpression on intestinal inflammation and the development of fibrostenosis. We assessed the in vivo consequences of constitutive TL1A expression on gut mucosal inflammation and fibrostenosis using two murine models of chronic colitis. In the dextran sodium sulfate (DSS) and adoptive T-cell transfer models, there was proximal migration of colonic inflammation, worsened patchy intestinal inflammation, and long gross intestinal strictures in Tl1a transgenic compared to wild-type littermates. In the DSS model, myeloid- and T-cell-expressing Tl1a transgenic mice had increased T-cell activation markers and interleukin-17 expression compared to wild-type mice. In the T-cell transfer model, Rag1(-/-) mice receiving Tl1a transgenic T cells had increased interferon-γ expression but reduced T-helper 17 cells and IL-17 production. Narrowed ureters with hydronephrosis were found only in the Tl1a transgenic mice in all chronic colitis models. In human translational studies, Crohn's disease patients with higher peripheral TL1A expression also exhibited intestinal fibrostenosis and worsened ileocecal inflammation with relative sparing of rectosigmoid inflammation. These data show that TL1A is an important cytokine that not only modulates the location and severity of mucosal inflammation, but also induces fibrostenosis.
authors.affiliation: Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Robert
authors.initials: R
authors.lastname: Barrett
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Zhang
authors.forename: Hon Wai
authors.initials: HW
authors.lastname: Koon
authors.forename: Michelle
authors.initials: M
authors.lastname: Vu
authors.forename: Jyh-Yau
authors.initials: JY
authors.lastname: Chang
authors.forename: Nicole
authors.initials: N
authors.lastname: Yeager
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Nguyen
authors.forename: Kathrin S
authors.initials: KS
authors.lastname: Michelsen
authors.forename: Dror
authors.initials: D
authors.lastname: Berel
authors.forename: Charalabos
authors.initials: C
authors.lastname: Pothoulakis
authors.forename: Stephan R
authors.initials: SR
authors.lastname: Targan
authors.forename: David Q
authors.initials: DQ
authors.lastname: Shih
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002908:Chronic Disease; D003092:Colitis / Q000209:etiology* / Q000473:pathology; D003106:Colon / Q000378:metabolism / Q000473:pathology*; D003251:Constriction, Pathologic / Q000209:etiology; D005355:Fibrosis / Q000209:etiology; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009195:Peroxidase / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000378:metabolism*
chemical_list: D020381:Interleukin-17; C117026:TNFSF15 protein, human; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D009195:Peroxidase