The tumor necrosis factor family member TNFSF14 (LIGHT) is required for resolution of intestinal inflammation in mice.

Abstract

BACKGROUND & AIMS:

The pathogenesis of inflammatory bowel disease (IBD) is associated with a dysregulated mucosal immune response. Expression of the tumor necrosis factor (TNF) superfamily member 14 (TNFSF14, also known as LIGHT [homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes]) on T cells is involved in their activation; transgenic expression of LIGHT on T cells in mice promotes inflammation in multiple organs, including intestine. We investigated the roles for LIGHT in recovery from intestinal inflammation in mice.

METHODS:

We studied the role of LIGHT in intestinal inflammation using Tnfsf14(-/-) and wild-type mice. Colitis was induced by transfer of CD4(+)CD45RB(high) T cells into Rag1(-/-) or Tnfsf14(-/-)Rag1(-/-) mice, or by administration of dextran sulfate sodium to Tnfsf14(-/-) or wild-type C57BL/6J mice. Mice were weighed, colon tissues were collected and measured, and histology analyses were performed. We measured infiltrating cell populations and expression of cytokines, chemokines, and LIGHT.

RESULTS:

After administration of dextran sulfate sodium, Tnfsf14(-/-) mice developed more severe colitis than controls, based on their reduced survival, accelerated loss of body weight, and histologic scores. LIGHT protected mice from colitis via the lymphotoxin β receptor and was expressed mainly by myeloid cells in the colon. Colons of Tnfsf14(-/-) mice also had increased accumulation of innate immune cells and higher levels of cytokines than colons from control mice. LIGHT, therefore, appears to regulate inflammation in the colon.

CONCLUSIONS:

Tnfsf14(-/-) mice develop more severe colitis than control mice. LIGHT signals through the lymphotoxin β receptor in the colon to regulate the innate immune response and mediate recovery from intestinal inflammation.

• Authors: Petra Krause, Sonja P Zahner, Gisen Kim, Raziyah B Shaikh, Marcos W Steinberg, Mitchell Kronenberg
• Journal: Gastroenterology (Gastroenterology) Vol. 146 Issue 7 Pg. 1752-62.e4 (Jun 2014) ISSN: 1528-0012 [Electronic] United States
• PMID: 24560868 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• Cytokines
• Homeodomain Proteins
• Inflammation Mediators
• Ltbr protein, mouse
• Lymphotoxin beta Receptor
• Tnfsf14 protein, mouse
• Tumor Necrosis Factor Ligand Superfamily Member 14
• RAG-1 protein
• Dextran Sulfate
• Leukocyte Common Antigens
• PTPRC protein, human

Topics

• Animals
• CD4-Positive T-Lymphocytes (immunology, metabolism, pathology, transplantation)
• Colitis (chemically induced, immunology, metabolism, pathology, prevention & control)
• Colon (immunology, metabolism, pathology)
• Cytokines (metabolism)
• Dextran Sulfate
• Disease Models, Animal
• Homeodomain Proteins (genetics, metabolism)
• Immunity, Innate
• Inflammation Mediators (metabolism)
• Intestinal Mucosa (immunology, metabolism, pathology)
• Leukocyte Common Antigens (metabolism)
• Lymphotoxin beta Receptor (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Severity of Illness Index
• Signal Transduction
• Time Factors
• Tumor Necrosis Factor Ligand Superfamily Member 14 (deficiency, genetics, metabolism)
• Weight Loss