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


CONCLUSIONS
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.
DeLay
Monica L
ML
Cincinnati Children's Hospital Medical Center, and University of Cincinnati College of Medicine, Cincinnati, Ohio.
Turner
Matthew J
MJ
Klenk
Erin I
EI
Smith
Judith A
JA
Sowders
Dawn P
DP
Colbert
Robert A
RA
D000818:Animals; D002478:Cells, Cultured; D003106:Colon / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D015796:HLA-B27 Antigen / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism*; D053759:Interleukin-23 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011487:Protein Conformation; D051381:Rats; D011916:Rats, Inbred F344; D055647:Rats, Transgenic; D025241:Spondylarthritis / Q000378:metabolism* / Q000473:pathology*; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism* / Q000473:pathology; D018417:Th1 Cells / Q000378:metabolism / Q000473:pathology; D001613:beta 2-Microglobulin / Q000235:genetics / Q000378:metabolism
D015796:HLA-B27 Antigen; D020381:Interleukin-17; D053759:Interleukin-23; D008070:Lipopolysaccharides; D001613:beta 2-Microglobulin