Interferon- Contributes to HLA-B27-associated Unfolded Protein Response in Spondyloarthropathies

Department of Clinical Immunology, State Key Discipline of Cell Biology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, China.
The Journal of Rheumatology (Impact Factor: 3.19). 03/2012; 39(3):574-82. DOI: 10.3899/jrheum.101257
Source: PubMed


HLA-B27 positivity strongly influences the susceptibility to and phenotype of spondyloarthropathies (SpA). This study was designed to screen factors that activate the promoter of HLA-B27 in U937 cells, and to assess whether these promoter-activating factors induce the unfolded protein response (UPR) in HLA-B27-expressing cells.
Cytometric Bead Array, flow cytometry, and real-time polymerase chain reaction were used to detect the expression of cytokines and UPR-associated proteins in peripheral blood and synovial fluid of patients with SpA. The HLA-B27 promotor transfectant was incubated separately with cytokines and Toll-like receptor ligands. After interferon-γ (IFN-γ) stimulation, expressions of GRP78, CHOP, and XBP-1 were tested in HLA-B27-expressing U937 cells and peripheral blood mononuclear cell (PBMC) of patients with ankylosing spondylitis (AS). (Clinical trial registration no. ChiCTR-OCC-11001565)
Expressions of GRP78, CHOP, and XBP-1 in monocytes/macrophages of SpA peripheral blood and synovial fluid were higher than those in healthy controls and patients with osteoarthritis (OA) (p < 0.05). Tumor necrosis factor-α (TNF-α) and IFN-α, IFN-ß, and IFN-γ were found to have activated the HLA-B27 promoter in the U937 cell line (p < 0.05). Following stimulation with IFN-γ, the expressions of GRP78, CHOP and XBP-1 in HLA-B27-transfected U937 cells and PBMC of HLA-B27-positive AS patients were more intense than those in A2-U937 cells, HLA-B27-negative AS patients, or healthy controls (p < 0.05).
Expressions of GRP78, CHOP, and XBP-1 were higher in monocytes/macrophages of patients with SpA than those in both OA patients and healthy controls, suggesting that UPR may participate in the pathogenesis of SpA. TNF-α and IFN-α, IFN-ß, and IFN-γ significantly activated HLA-B27 promoter in the U937 cell line, and IFN-γ, the strongest activating factor, may induce the UPR in HLA-B27-expressing cells.

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    • "Structurally, the molecule differs from other HLA molecules due to slow folding heavy chains, which form aberrant dimers [41, 42]. It is thought that these aberrant dimers accumulate within cells leading to increased unfolded protein response (UPR) that activates the stress response in cells [43, 44]. Markers of the UPR were associated with increased exposure to proinflammatory cytokines such as IFN-γ [43]. "
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