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.
Jungbeck
Michaela
M
Institute of Immunology, University of Regensburg, Franz-Josef-Strauss-Allee 11, D-93042 Regensburg, Germany.
Stopfer
Peter
P
Bataille
Frauke
F
Nedospasov
Sergei A
SA
Männel
Daniela N
DN
Hehlgans
Thomas
T
D000208:Acute Disease; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D003092:Colitis / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D007136:Immunoglobulins / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism; D008024:Ligands; D053259:Lymphotoxin beta Receptor / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism; D053308:Lymphotoxin-beta / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009195:Peroxidase / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D015431:Weight Loss / Q000187:drug effects
D007136:Immunoglobulins; D008024:Ligands; D053259:Lymphotoxin beta Receptor; D053308:Lymphotoxin-beta; D009195:Peroxidase