The Tumor Necrosis Factor Family Member TNFSF14 (LIGHT) Is Required for Resolution of Intestinal Inflammation in Mice

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.