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

Arthritis Rheum. 2009 Sep;60(9):2633-43. doi: 10.1002/art.24763.


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 (Hubeta(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/Hubeta(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/Hubeta(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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Colon / metabolism
  • Colon / pathology
  • Disease Models, Animal
  • HLA-B27 Antigen / chemistry*
  • HLA-B27 Antigen / genetics
  • HLA-B27 Antigen / metabolism*
  • Humans
  • Interleukin-17 / metabolism*
  • Interleukin-23 / metabolism*
  • Lipopolysaccharides / pharmacology
  • Macrophages / metabolism
  • Macrophages / pathology
  • Mice
  • Mice, Inbred C57BL
  • Protein Conformation
  • Rats
  • Rats, Inbred F344
  • Rats, Transgenic
  • Spondylarthritis / metabolism*
  • Spondylarthritis / pathology*
  • T-Lymphocytes, Helper-Inducer / metabolism*
  • T-Lymphocytes, Helper-Inducer / pathology
  • Th1 Cells / metabolism
  • Th1 Cells / pathology
  • beta 2-Microglobulin / genetics
  • beta 2-Microglobulin / metabolism


  • HLA-B27 Antigen
  • Interleukin-17
  • Interleukin-23
  • Lipopolysaccharides
  • beta 2-Microglobulin