The lymphotoxin-β receptor is critical for control of murine Citrobacter rodentium-induced colitis

Thomas W. Spahn, Christian Maaser, Lars Eckmann, Jan Heidemann, Andreas Lügering, Rodney Newberry, Wolfram Domschke, Hermann Herbst, Torsten Kucharzik

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1463-1473
Number of pages11
JournalGastroenterology
Volume127
Issue number5
DOIs
StatePublished - Nov 2004

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