HLA–B27 misfolding and the unfolded protein response augment interleukin‐23 production and are associated with Th17 activation in transgenic rats

Abstract

AbstractObjectiveTo 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.MethodsCytokine 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.ResultsInterleukin‐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.ConclusionThe 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.