Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology.
The CD40-CD154 pathway is important in the pathogenesis of inflammatory bowel disease. Here we show that injection of an agonistic CD40 mAb to T and B cell-deficient mice was sufficient to induce a pathogenic systemic and intestinal innate inflammatory response that was functionally dependent on tumor necrosis factor-alpha and interferon-gamma as well as interleukin-12 p40 and interleukin-23 p40 secretion. CD40-induced colitis, but not wasting disease or serum proinflammatory cytokine production, depended on interleukin-23 p19 secretion, whereas interleukin-12 p35 secretion controlled wasting disease and serum cytokine production but not mucosal immunopathology. Intestinal inflammation was associated with IL-23 (p19) mRNA-producing intestinal dendritic cells and IL-17A mRNA within the intestine. Our experiments identified IL-23 as an effector cytokine within the innate intestinal immune system. The differential role of IL-23 in local but not systemic inflammation suggests that it may make a more specific target for the treatment of IBD.
Uhlig
Holm H
HH
Sir William Dunn School of Pathology, University of Oxford, South Parks Road, OX1 3RE Oxford, UK.
McKenzie
Brent S
BS
Hue
Sophie
S
Thompson
Claire
C
Joyce-Shaikh
Barbara
B
Stepankova
Renata
R
Robinson
Nicolas
N
Buonocore
Sofia
S
Tlaskalova-Hogenova
Helena
H
Cua
Daniel J
DJ
Powrie
Fiona
F
D000818:Animals; D000906:Antibodies / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology; D003092:Colitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007113:Immunity, Innate / Q000276:immunology*; D018928:Immunity, Mucosal / Q000276:immunology*; D018664:Interleukin-12 / Q000276:immunology*; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity; D013154:Spleen / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D019282:Wasting Syndrome / Q000276:immunology / Q000473:pathology
D000906:Antibodies; D019013:CD40 Antigens; C508841:Il23a protein, mouse; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D018664:Interleukin-12