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Altered PKR Signalling and C / EBPβ Expression is Associated with HLA-B27 Expression in Monocytic Cells
A S Sahlberg1, M Ruuska1, R A Colbert1
1National Institute for Health and Welfare, Turku, FinlandNIAMS, National Institutes of Health, Bethesda, MD, USADepartment of Medical Microbiology, University of Turku, Turku, Finland.
Scandinavian Journal of Immunology
|October 13, 2011
Summary
Human leukocyte antigen B27 (HLA-B27) expression alters double-stranded RNA-activated kinase (PKR) signaling pathways in Salmonella-infected cells. This disruption, linked to HLA-B27
Area of Science:
- Immunology
- Microbiology
- Molecular Biology
Background:
- Reactive arthritis (ReA) is an inflammatory joint disease triggered by gram-negative bacterial infections like Salmonella.
- ReA development is strongly associated with the human leukocyte antigen B27 (HLA-B27) tissue antigen.
- Persistent bacteria or bacterial components are implicated in ReA pathogenesis.
Purpose of the Study:
- To investigate the role of HLA-B27 in regulating double-stranded RNA-activated kinase (PKR)-related signaling pathways.
- To examine the impact of HLA-B27 on Salmonella-infected or lipopolysaccharide (LPS)-stimulated human monocytic cells (U937).
Main Methods:
- Utilized human U937 monocytic cells expressing HLA-B27.
- Infected cells with Salmonella or stimulated with Salmonella lipopolysaccharide (LPS).
- Analyzed the expression and phosphorylation status of PKR and CCAAT enhancer binding protein beta (C/EBPβ).
Main Results:
- HLA-B27 expression led to overexpression and hypophosphorylation of PKR in infected/stimulated cells.
- Salmonella infection and LPS stimulation increased C/EBPβ expression in HLA-B27 expressing cells.
- C/EBPβ expression was PKR-dependent in mock cells but largely PKR-independent in HLA-B27 expressing cells upon LPS stimulation.
Conclusions:
- HLA-B27 expression significantly disturbs PKR-mediated signaling pathways.
- Altered signaling is associated with misfolding of the HLA-B27 heavy chain (Glu45 in the B pocket).
- HLA-B27 modulates the intracellular environment and bacterial elimination mechanisms in monocytes/macrophages, potentially via misfolding-dependent signaling alterations.
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