Ankylosing spondylitis macrophage production of higher levels of interleukin‐23 in response to lipopolysaccharide without induction of a significant unfolded protein …

L Zeng, MJ Lindstrom, JA Smith - Arthritis & Rheumatism, 2011 - Wiley Online Library
L Zeng, MJ Lindstrom, JA Smith
Arthritis & Rheumatism, 2011Wiley Online Library
Objective Previous studies of the HLA–B27–transgenic rat model of ankylosing spondylitis
(AS) suggested that macrophages develop an intracellular stress response called the
unfolded protein response (UPR) and, as a result, secrete increased amounts of cytokines in
response to Toll‐like receptor agonists such as lipopolysaccharide (LPS). Our objective was
to determine whether macrophages from AS patients also undergo a UPR and secrete
increased cytokines/chemokines in response to LPS. Methods Peripheral blood monocytes …
Objective
Previous studies of the HLA–B27–transgenic rat model of ankylosing spondylitis (AS) suggested that macrophages develop an intracellular stress response called the unfolded protein response (UPR) and, as a result, secrete increased amounts of cytokines in response to Toll‐like receptor agonists such as lipopolysaccharide (LPS). Our objective was to determine whether macrophages from AS patients also undergo a UPR and secrete increased cytokines/chemokines in response to LPS.
Methods
Peripheral blood monocytes isolated from 10 AS patients and 10 healthy controls were differentiated in vitro with macrophage colony‐stimulating factor. Select samples were treated with interferon‐γ (IFNγ) to up‐regulate class I major histocompatibility complex (HLA–B) expression prior to stimulation with LPS for either 3 hours (for RNA) or 8–24 hours (for supernatant). UPR induction was assessed by measuring the expression of messenger RNA for ERdj4, BiP, and CCAAT/enhancer binding protein homologous protein 10 (CHOP).
Results
Although IFNγ treatment up‐regulated HLA–B expression (2‐fold; P < 0.0001), neither IFNγ nor LPS substantially enhanced BiP or CHOP expression (<1.3‐fold). ERdj4 expression increased weakly, but not significantly, in AS samples treated with IFNγ plus LPS (2.2‐fold; P = 0.31). In response to LPS, AS macrophages secreted more CXCL9, interleukin‐10 (IL‐10), IL‐12p70, IL‐23, and tumor necrosis factor α than did control macrophages (P ≤ 0.025). The most striking difference was observed for IL‐23 (median 265 pg/ml in AS patients versus 9 pg/ml in controls; P = 0.0007). We did not detect significant differences in IL‐6, IL‐8, or IFNβ production.
Conclusion
The greater production of IL‐23 by AS patient macrophages in response to LPS provides further support for the development of Th17/IL‐23–directed therapy. Since significant UPR induction was not detected in AS patient macrophages, the relationship between UPR and inflammatory cytokine production remains unclear.
Wiley Online Library