HLA-B27 Misfolding and the Unfolded Protein Response Augment Interleukin-23 Production and Are Associated With Th17 Activation in Transgenic Rats

被引:304
作者
Delay, Monica L.
Turner, Matthew J.
Klenk, Erin I.
Smith, Judith A.
Sowders, Dawn P.
Colbert, Robert A.
机构
[1] Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA
[2] Univ Cincinnati, Coll Med, Cincinnati, OH USA
来源
ARTHRITIS AND RHEUMATISM | 2009年 / 60卷 / 09期
关键词
ENDOPLASMIC-RETICULUM STRESS; T-CELLS; ANKYLOSING-SPONDYLITIS; HLA-B27-TRANSGENIC RATS; AUTOIMMUNE INFLAMMATION; INTESTINAL INFLAMMATION; INTERFERON-GAMMA; CHRONIC COLITIS; IFN-GAMMA; ARTHRITIS;
D O I
10.1002/art.24763
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective. To determine whether HLA-B27 misfolding and the unfolded protein response (UPR) result in cytokine dysregulation and whether this is associated with Th1 and/or Th17 activation in HLA-B27/human beta(2)-microglobulin (Hu beta(2)m)-transgenic rats, an animal model of spondylarthritis. Methods. Cytokine expression in lipopolysaccharide (LPS)-stimulated macrophages was analyzed in the presence and absence of a UPR induced by chemical agents or by HLA-B27 up-regulation. Cytokine expression in colon tissue and in cells purified from the lamina propria was determined by real-time reverse transcription-polymerase chain reaction analysis, and differences in Th1 and Th17 CD4+ T cell populations were quantified after intracellular cytokine staining. Results. Interleukin-23 (IL-23) was found to be synergistically up-regulated by LPS in macrophages undergoing a UPR induced by pharmacologic agents or by HLA-B27 misfolding. IL-23 was also increased in the colon tissue from B27/Hu beta(2)m-transgenic rats concurrently with the development of intestinal inflammation, and IL-17, a downstream target of IL-23, exhibited robust up-regulation in a similar temporal pattern. IL-23 and IL-17 transcripts were localized to CD11+ antigen-presenting cells and CD4+ T cells, respectively, from the colonic lamina propria. Colitis was associated with a 6-fold expansion of CD4+ IL-17-expressing T cells. Conclusion. The IL-23/IL-17 axis is strongly activated in the colon of B27/Hu beta(2)m-transgenic rats with spondylarthritis-like disease. HLA-B27 misfolding and UPR activation in macrophages can result in enhanced induction of the pro-Th17 cytokine IL-23. These results suggest a possible link between HLA-B27 misfolding and immune dysregulation in this animal model, with implications for human disease.
引用
收藏
页码:2633 / 2643
页数:11
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