Type

Journal Article

Authors

Caroline A Jefferies
Grainne Kearns
Lorraine O'Neill
Peter Browne
James Johnston
Aubrey Bell
Elizabeth Ball
Antonio Sica
Maria Grazia Totaro
Alexander Espinosa
and 5 others

Subjects

Biochemistry

Topics
chromatin immunoprecipitation poly i c animals mice protein serine threonine kinases irf3 protein mouse mice knockout tbk1 protein mouse macrophages interleukin 23 subunit p19 metabolism humans drug effects gene expression regulation protein array analysis immunology female protein binding genetics interferon regulatory factor 3 lupus erythematosus systemic male bone marrow cells tbk1 protein human monocytes disease models animal pharmacology toll like receptor 3 mice inbred c57bl irf3 protein human

Enhanced interferon regulatory factor 3 binding to the interleukin-23p19 promoter correlates with enhanced interleukin-23 expression in systemic lupus erythematosus. (2011)

Abstract To examine the role of interferon regulatory factor 3 (IRF-3) in the regulation of interleukin-23 (IL-23) production in patients with systemic lupus erythematosus (SLE). Bone marrow-derived macrophages were isolated from both wild-type and IRF3(-/-) C57BL/6 mice. These cells were stimulated with the Toll-like receptor 3 (TLR-3) agonist poly(I-C), and IL-23p19 cytokine levels were analyzed by enzyme-linked immunosorbent assay. IRF-3 binding to the IL-23p19 gene promoter region in monocytes from patients with SLE and healthy control subjects was analyzed by chromatin immunoprecipitation (ChIP) assay. Luciferase reporter gene assays were performed to identify key drivers of IL-23p19 promoter activity. TANK-binding kinase 1 (TBK-1) protein levels were determined by Western blotting. ChIP assays demonstrated that IRF-3 was stably bound to the human IL-23p19 promoter in monocytes; this association increased following TLR-3 stimulation. Patients with SLE demonstrated increased levels of IRF-3 bound to the IL-23p19 promoter compared with control subjects, which correlated with enhanced IL-23p19 production in monocytes from patients with SLE. Investigations of the TLR-3-driven responses in monocytes from patients with SLE revealed that TBK-1, which is critical for regulating IRF-3 activity, was hyperactivated in both resting and TLR-3-stimulated cells. Our results demonstrate for the first time that patients with SLE display enhanced IL-23p19 expression as a result of hyperactivation of TBK-1, resulting in increased binding of IRF-3 to the promoter. These findings provide novel insights into the molecular pathogenesis of SLE and the potential role for TLR-3 in driving this response.
Collections Ireland -> Royal College of Surgeons in Ireland -> PubMed

Full list of authors on original publication

Caroline A Jefferies, Grainne Kearns, Lorraine O'Neill, Peter Browne, James Johnston, Aubrey Bell, Elizabeth Ball, Antonio Sica, Maria Grazia Totaro, Alexander Espinosa and 5 others

Experts in our system

1
Caroline A Jefferies
Royal College of Surgeons in Ireland
Total Publications: 50
 
2
Grainne Kearns
Royal College of Surgeons in Ireland
Total Publications: 6
 
3
James A Johnston
Trinity College Dublin
Total Publications: 10