Role of TL1A and its receptor DR3 in two models of chronic murine ileitis

被引:136
作者
Bamias, Giorgos
Mishina, Margarita
Nyce, Mark
Ross, William G.
Kollias, Giorgos
Rivera-Nieves, Jesus
Pizarro, Theresa T.
Cominelli, Fabio
机构
[1] Univ Virginia, Hlth Sci Ctr, Digest Hlth Ctr Excellence, Charlottesville, VA 22908 USA
[2] Alexander Fleming Biomed Sci Res Ctr, Inst Immunol, Vari 16672, Greece
关键词
Crohn's disease; cytokines; mucosal inflammation;
D O I
10.1073/pnas.0510903103
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
TL1A is a TNF-like cytokine that binds to the death-domain receptor (DR)3 and provides costimulatory signals to activated lymphocytes. Through this interaction, TL1A induces secretion of IFN-gamma and may, therefore, participate in the development of T helper-1-type effector responses. In this study, we investigated whether interactions between TL1A and DR3 are involved in the pathogenesis of chronic murine ileitis. We demonstrate that alternative splicing of DR3 mRNA takes place during the activation of lymphocytes, which results in up-regulation of the complete/transmembrane (tm) form of DR3. Using two immunogenetically distinct animal models of Crohn's disease, we demonstrate that induction of intestinal inflammation is associated with significant up-regulation of TL1A and tm DR3 in the inflamed mucosa. in addition, within isolated lamina propria mononuclear cells from mice with inflammation, TL1A is primarily expressed on CD11c(high) dendritic cells. We also report that TL1A acts preferentially on memory CD4(+)/CD45RB(lo) murine lymphocytes by significantly inducing their proliferation, whereas it does not affect the proliferation of the naive CD4(+)/ CD45RB(hi) T helper cell subpopulation. Finally, we demonstrate that TL1A synergizes with both the cytokine-dependent IL-12/IL-18 pathway and with low-dose stimulation of the T cell receptor to significantly induce the secretion of IFN-gamma via an IL-18-independent pathway. Our results raise the possibility that interaction(s) between TL1A expressed on antigen-presenting cells and tm DR3 on lymphocytes may be of particular importance for the pathogenesis of chronic inflammatory conditions that depend on IFN-gamma secretion, including inflammatory bowel disease. Blockade of the TL1A/DR3 pathway may, therefore, offer therapeutic opportunities in Crohn's disease.
引用
收藏
页码:8441 / 8446
页数:6
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