Neutralization of LIGHT ameliorates acute dextran sodium sulphate-induced intestinal inflammation.

Emerging data indicate that alterations in the expression of tumour necrosis factor (TNF) superfamily members play a crucial role in the pathogenesis of intestinal inflammation. Recent results demonstrated that sustained transgenic expression of lymphotoxin-like inducible protein that competes with glycoprotein D for binding herpesvirus entry mediator on T cells (LIGHT; TNFSF14) induced severe intestinal inflammation, suggesting a specific role of LIGHT-mediated signalling to the intestinal compartment. In order to dissect the role of LIGHT in intestinal inflammation, we used LIGHT-deficient mice in the mouse model of acute dextran sodium sulphate-induced colitis. Interestingly, LIGHT-deficient mice were characterized by strongly reduced signs of intestinal inflammation compared with wild-type mice in this experimental model. Determination of mouse LIGHT mRNA expression in colon tissues of wild-type mice revealed a strong induction of mouse LIGHT mRNA expression during acute DSS-induced colitis. We therefore generated anti-mouse LIGHT monoclonal antibodies in LIGHT-deficient mice which bind specifically to LIGHT and are capable of neutralizing the activity of LIGHT in vitro and in vivo. With these antibodies, we demonstrated that neutralization of LIGHT during acute DSS-induced colitis resulted in reduced signs of intestinal inflammation. These data suggest that LIGHT is an important mediator in intestinal inflammation and may serve as a new target for therapeutic intervention.

Blocking lymphotoxin beta receptor signalling exacerbates acute DSS-induced intestinal inflammation--opposite functions for surface lymphotoxin expressed by T and B lymphocytes.

The lymphotoxin beta receptor (LTbetaR) signalling pathway is involved in the development of secondary lymphoid organs and the maintenance of organized lymphoid tissues. Additionally, previous studies clearly demonstrated the involvement of the LTbetaR interaction with its ligands in promoting intestinal inflammation. In order to dissect the role of LTbetaR activation in the mouse model of acute DSS-induced colitis we treated mice with a functional inhibitor of LTbetaR activation (LTbetaR:Ig) and compared it to disease in LTbetaR-deficient and LTalphabeta-deficient mice. All these modes of LTbetaR signalling ablation resulted in significant aggravation of the disease and in release of inflammatory cytokines such as TNF, IL-6, and IFNgamma. Finally, using mice with conditionally ablated expression of membrane bound LTbeta on T or B cells, respectively, distinct and opposite contributions of surface LTbeta expressed on T or B cells was found. Thus, activation of LTbetaR by LTalphabeta mainly expressed on T lymphocytes is crucial for the down regulation of the inflammatory response in this experimental model.