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 (LT beta R) 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 LT beta R interaction with its ligands in promoting intestinal inflammation. In order to dissect the role of LT beta R activation in the mouse model of acute DSS-induced colitis we treated mice with a functional inhibitor of LT beta R activation (LT beta R:Ig) and compared it to disease in LT beta R-deficient and LT alpha beta-deficient mice. All these modes of LT beta R signalling ablation resulted in significant aggravation of the disease and in release of inflammatory cytokines such as TNF, IL-6, and IFN-gamma. Finally, using mice with conditionally ablated expression of membrane bound LT beta on T or B cells, respectively, distinct and opposite contributions of surface LT beta expressed on T or B cells was found. Thus, activation of LT beta R by LT alpha beta mainly expressed on T lymphocytes is crucial for the down regulation of the inflammatory response in this experimental model. (C) 2007 Elsevier Ltd. All rights reserved.