The lymphotoxin-beta receptor is critical for control of murine Citrobacter rodentium-induced colitis.
OBJECTIVE
Lymphotoxin is a tumor necrosis factor-family cytokine. Blocking of lymphotoxin alpha 1 beta 2 /lymphotoxin-beta 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 alpha 1 beta 2 /lymphotoxin-beta receptor signaling in Citrobacter rodentium -induced colitis.


METHODS
Mice with disrupted lymphotoxin alpha 1 beta 2 /lymphotoxin-beta receptor interactions secondary to gene defects (lymphotoxin-alpha -/- , lymphotoxin-beta -/- , and lymphotoxin-beta receptor -/- ) or treatment with the antagonist lymphotoxin-beta 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 alpha 1 beta 2 /lymphotoxin-beta 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-beta receptor-immunoglobulin G-treated mice. There was a reduction of CD11c + dendritic cells in the spleen of naive and infected -/- and lymphotoxin-beta receptor-immunoglobulin G-treated mice. In infected lymphotoxin-beta 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-beta receptor -/- mice.


CONCLUSIONS
Lymphotoxin alpha 1 beta 2 /lymphotoxin-beta receptor interactions are critical for immunity against Citrobacter rodentium in mice. Impaired anti-enteropathogenic Escherichia coli immunity may be anticipated in anti-lymphotoxin-beta receptor-directed therapy for human inflammatory bowel disease.
Spahn
Thomas W
TW
Department of Medicine, Münster University Hospital, Münster, Germany. spahn@uni-muenster.de
Maaser
Christian
C
Eckmann
Lars
L
Heidemann
Jan
J
Lügering
Andreas
A
Newberry
Rodney
R
Domschke
Wolfram
W
Herbst
Hermann
H
Kucharzik
Torsten
T
D000818:Animals; D044082:Citrobacter rodentium; D003092:Colitis / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D004756:Enterobacteriaceae Infections / Q000276:immunology* / Q000473:pathology; D005434:Flow Cytometry; D018928:Immunity, Mucosal; D007074:Immunoglobulin G / Q000276:immunology; D007150:Immunohistochemistry; D053259:Lymphotoxin beta Receptor; D051379:Mice; D008810:Mice, Inbred C57BL; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000032:analysis
D007074:Immunoglobulin G; C505697:LTBR protein, human; C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins