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

• Published in: Molecular immunology Vol. 45; no. 1; pp. 34 - 41
• Main Authors: Jungbeck, Michaela, Stopfer, Peter, Bataille, Frauke, Nedospasov, Sergei A., Männel, Daniela N., Hehlgans, Thomas
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.01.2008
• Subjects: Acute Disease; Animals; B-Lymphocytes - drug effects; B-Lymphocytes - metabolism; Colitis - chemically induced; Colitis - enzymology; Colitis - metabolism; Colitis - pathology; Conditional LTβ-deficient mice; Disease Models, Animal; DSS-induced intestinal inflammation; Female; Immunoglobulins - pharmacology; Inflammation - metabolism; Ligands; LTαβ; LTβR; LTβR:Ig; Lymphotoxin beta Receptor - antagonists & inhibitors; Lymphotoxin beta Receptor - deficiency; Lymphotoxin beta Receptor - metabolism; Lymphotoxin-beta - metabolism; Mice; Mice, Inbred C57BL; Peroxidase - metabolism; Signal Transduction - drug effects; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; Weight Loss - drug effects; Conditional LTβ-deficient mice; LTβR:Ig; DSS-induced intestinal inflammation; LTβR; LTαβ
• ISSN: 0161-5890; 1872-9142
• DOI: 10.1016/j.molimm.2007.05.007

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