Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology

被引:583
作者
Uhlig, Holm H.
McKenzie, Brent S.
Hue, Sophie
Thompson, Claire
Joyce-Shaikh, Barbara
Stepankova, Renata
Robinson, Nicolas
Buonocore, Sofia
Tlaskalova-Hogenova, Helena
Cua, Daniel J.
Powrie, Fiona
机构
[1] Schering Plough Biopharma, Palo Alto, CA 94304 USA
[2] Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RE, England
[3] Acad Sci Czech Republ, Inst Microbiol & Gnotobiol, Prague 54922, Czech Republic
[4] Acad Sci Czech Republ, Inst Microbiol & Gnotobiol, Novy Hradek, Czech Republic
基金
英国惠康基金;
关键词
D O I
10.1016/j.immuni.2006.05.017
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:309 / 318
页数:10
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