The Tumor Necrosis Factor Superfamily Members TNFSF14 (LIGHT), Lymphotoxin β and Lymphotoxin β Receptor Interact to Regulate Intestinal Inflammation

Abstract

Over 1.5 million individuals in the United States are afflicted with inflammatory bowel disease (IBD). While the progression of IBD is multifactorial, chronic, unresolved inflammation certainly plays a key role. Additionally, while multiple immune mediators have been shown to affect pathogenesis, a comprehensive understanding of disease progression is lacking. Previous work has demonstrated that a member of the TNF superfamily, TNFSF14 (LIGHT), which is pro-inflammatory in several contexts, surprisingly plays an important role in protection from inflammation in mouse models of colitis, with LIGHT deficient mice having more severe disease pathogenesis. However, LIGHT is a single member of a complex signaling network. It signals through multiple receptors, including herpes virus entry mediator (HVEM) and lymphotoxin beta receptor (LTβR); these two receptors in turn can bind to other ligands. It remains unknown which receptors and competing ligands can mediate or counteract the outcome of LIGHT-signaling during colitis. Here we demonstrate that LIGHT signaling through LTβR, rather than HVEM, plays a critical role in the progression of DSS-induced colitis, as LTβR deficient mice exhibit a more severe disease phenotype. Further, mice deficient in LTαβ do not exhibit differential colitis progression compared to WT mice. However, deletion of both LIGHT and LTαβ, but not deletion of both LTαβ and LTβR, resulted in a reversal of the adverse effects associated with the loss of LIGHT. In sum, the LIGHT/LTαβ/LTβR signaling network contributes to DSS colitis, but there may be additional receptors or indirect effects, and therefore, the relationships between these receptors and ligands remains enigmatic.

High‐dose dietary supplementation with zinc prevents gut inflammation: Investigation of the role of metallothioneins and beyond by transcriptomic and metagenomic studies

“…A recent study has nevertheless shown that interactions with tumor necrosis factor superfamily members (including Ltb) contribute to colitis in the DSS model. 77 We found that expression of Scl30a2 (coding for ZnT2) was upregulated in the ileum-suggesting an increase in Zn transport into secretory vesicles. Podany et al reported that ZnT2 is responsible for the accumulation of Zn in Paneth cell granules and that this accumulation is necessary for the cells' coordinated secretion and function in mice.…”

Calebin A Potentiates the Effect of 5-FU and TNF-β (Lymphotoxin α) against Human Colorectal Cancer Cells: Potential Role of NF-κB

“…Intriguingly, several reports indicate that among stimulated pro-inflammatory cytokines, members of the Tumor Necrosis Factor (TNF) family are major players that participate in cancer progression [42,43]. Chronic intestinal inflammation is described to regulate expression and interaction of members of the TNF family such as TNF-α, TNF-β and LTβR acting as major mediators for CRC-related inflammation [44,45]. Moreover, our group has previously shown that TNF-β induces cancer progression and thus stimulates colorectal cancer cell malignity with the same potency as TNF-α [16,18,46].…”

TNFSF14: LIGHTing the Way for Effective Cancer Immunotherapy

“…The other receptor, LTβR, is found on the surface of epithelial, stromal, immature DC, and myeloid cells, but not on lymphocytes (14). During normal biological development LIGHT-LTβR interactions have been identified as a component of lymphoid structure development and maintenance (15).…”