TY - JOUR
T1 - The lymphotoxin-β receptor is critical for control of murine Citrobacter rodentium-induced colitis
AU - Spahn, Thomas W.
AU - Maaser, Christian
AU - Eckmann, Lars
AU - Heidemann, Jan
AU - Lügering, Andreas
AU - Newberry, Rodney
AU - Domschke, Wolfram
AU - Herbst, Hermann
AU - Kucharzik, Torsten
N1 - Funding Information:
Supported by grants from the Innovative Medizinische Forschung (SP 1 2 03 18; to T.W.S.), the University of Münster, the German Research Council (MA 2247/2-1; to C.M.), and the National Institutes of Health (AI56075; to L.E.).
PY - 2004/11
Y1 - 2004/11
N2 - Background & Aims: Lymphotoxin is a tumor necrosis factor-family cytokine. Blocking of lymphotoxin α1β2/ lymphotoxin-β receptor interactions prevents experimental colitis in mice, and this suggests a potential treatment principle of human inflammatory bowel disease. Infection of mice with Citrobacter rodentium serves as an animal model for human infectious colitis induced by enteropathogenic Escherichia coli. We studied the role of lymphotoxin α1β2/ lymphotoxin-β receptor signaling in Citrobacter rodentium-induced colitis. Methods: Mice with disrupted lymphotoxin α1β2/ lymphotoxin-β receptor interactions secondary to gene defects (lymphotoxin-α-/-, lymphotoxin-β-/-, and lymphotoxin-β receptor-/-) or treatment with the antagonist lymphotoxin-β receptor-immunoglobulin G fusion protein were infected with Citrobacter rodentium. Body weight, fecal excretion of Citrobacter rodentium, and disease-related mortality were monitored. Spleen and liver organ cultures of mice assessed systemic infection. Intestinal inflammation and lymphoid architecture were histologically recorded in the large intestine, mesenteric lymph nodes, and spleen of infected mice. Results: Inhibition of lymphotoxin α1β2/lymphotoxin-β receptor interactions was associated with increased severity of Citrobacter rodentium-induced colitis, as indicated by increased disease-related mortality, more severe weight loss, intestinal bacterial abscesses, and a higher burden of Citrobacter rodentium in the spleen and liver of -/- and lymphotoxin-β receptor-immunoglobulin G-treated mice. There was a reduction of CD11c+ dendritic cells in the spleen of naive and infected -/- and lymphotoxin-β receptor- immunoglobulin G-treated mice. In infected lymphotoxin-β receptor -/- mice, anti-Citrobacter rodentium immunoglobulin G2a levels were decreased, whereas immunoglobulin G1 levels were increased. Citrobacter rodentium-induced interleukin-4 secretion was increased in lymphotoxin-β receptor-/- mice. Conclusions: Lymphotoxin α1β 2/lymphotoxin-β receptor interactions are critical for immunity against Citrobacter rodentium in mice. Impaired anti-enteropathogenic Escherichia coli immunity may be anticipated in anti-lymphotoxin-β receptor-directed therapy for human inflammatory bowel disease.
AB - Background & Aims: Lymphotoxin is a tumor necrosis factor-family cytokine. Blocking of lymphotoxin α1β2/ lymphotoxin-β receptor interactions prevents experimental colitis in mice, and this suggests a potential treatment principle of human inflammatory bowel disease. Infection of mice with Citrobacter rodentium serves as an animal model for human infectious colitis induced by enteropathogenic Escherichia coli. We studied the role of lymphotoxin α1β2/ lymphotoxin-β receptor signaling in Citrobacter rodentium-induced colitis. Methods: Mice with disrupted lymphotoxin α1β2/ lymphotoxin-β receptor interactions secondary to gene defects (lymphotoxin-α-/-, lymphotoxin-β-/-, and lymphotoxin-β receptor-/-) or treatment with the antagonist lymphotoxin-β receptor-immunoglobulin G fusion protein were infected with Citrobacter rodentium. Body weight, fecal excretion of Citrobacter rodentium, and disease-related mortality were monitored. Spleen and liver organ cultures of mice assessed systemic infection. Intestinal inflammation and lymphoid architecture were histologically recorded in the large intestine, mesenteric lymph nodes, and spleen of infected mice. Results: Inhibition of lymphotoxin α1β2/lymphotoxin-β receptor interactions was associated with increased severity of Citrobacter rodentium-induced colitis, as indicated by increased disease-related mortality, more severe weight loss, intestinal bacterial abscesses, and a higher burden of Citrobacter rodentium in the spleen and liver of -/- and lymphotoxin-β receptor-immunoglobulin G-treated mice. There was a reduction of CD11c+ dendritic cells in the spleen of naive and infected -/- and lymphotoxin-β receptor- immunoglobulin G-treated mice. In infected lymphotoxin-β receptor -/- mice, anti-Citrobacter rodentium immunoglobulin G2a levels were decreased, whereas immunoglobulin G1 levels were increased. Citrobacter rodentium-induced interleukin-4 secretion was increased in lymphotoxin-β receptor-/- mice. Conclusions: Lymphotoxin α1β 2/lymphotoxin-β receptor interactions are critical for immunity against Citrobacter rodentium in mice. Impaired anti-enteropathogenic Escherichia coli immunity may be anticipated in anti-lymphotoxin-β receptor-directed therapy for human inflammatory bowel disease.
UR - http://www.scopus.com/inward/record.url?scp=7644235586&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2004.08.022
DO - 10.1053/j.gastro.2004.08.022
M3 - Article
C2 - 15521015
AN - SCOPUS:7644235586
SN - 0016-5085
VL - 127
SP - 1463
EP - 1473
JO - Gastroenterology
JF - Gastroenterology
IS - 5
ER -