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

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Version 2 2022-03-14, 16:23
Version 1 2019-11-22, 16:25
journal contribution
posted on 2019-11-22, 16:25 authored by Siobhán Smith, Joan Nı Gabhann, Rowan Higgs, Kevin Stacey, Marie Wahren-Herlenius, Alexander Espinosa, Maria Grazia Totaro, Antonio Sica, Elizabeth Ball, Aubrey Bell, James Johnston, Peter Browne, Lorraine O'Neill, Grainne Kearns, Caroline A. Jefferies

OBJECTIVE: 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).

METHODS: 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.

RESULTS: 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.

CONCLUSION: 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.

History

Comments

"This is the peer reviewed version of the following article: Smith S, Ni Gabhann J, Higgs R, Stacey K, Wahren-Herlenius M, Espinosa A, Totaro MG, Sica A, Ball E, Bell A, Johnston J, Browne P, O'Neill L, Kearns G, Jefferies CA. Enhanced interferon regulatory factor 3 binding to the interleukin-23p19 promoter correlates with enhanced interleukin-23 expression in systemic lupus erythematosus. Arthritis and Rheumatism 2012;64(5)1601-1609. which has been published in final form at DOI: 10.1002/art.33494. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving."

Published Citation

Smith S, Ni Gabhann J, Higgs R, Stacey K, Wahren-Herlenius M, Espinosa A, Totaro MG, Sica A, Ball E, Bell A, Johnston J, Browne P, O'Neill L, Kearns G, Jefferies CA. Enhanced interferon regulatory factor 3 binding to the interleukin-23p19 promoter correlates with enhanced interleukin-23 expression in systemic lupus erythematosus. Arthritis and Rheumatism 2012;64(5)1601-1609.

Publication Date

2012-05-01

Publisher

Wiley-Liss, Inc.

PubMed ID

22127978