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 β2-microglobulin (Huβ2m)–transgenic rats, an animal model of spondylarthritis.
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.
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/Huβ2m-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.
The IL-23/IL-17 axis is strongly activated in the colon of B27/Huβ2m-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.