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Arthritis Rheum. 2011 Nov;63(11):3253-62. doi: 10.1002/art.30583.

Blocking of interferon regulatory factor 1 reduces tumor necrosis factor α-induced interleukin-18 bioactivity in rheumatoid arthritis synovial fibroblasts by induction of interleukin-18 binding protein a: role of the nuclear interferon regulatory factor 1-NF-κB-c-jun complex.

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1
University of Michigan Medical School, Ann Arbor, MI, USA.

Abstract

OBJECTIVE:

To examine the role of interferon regulatory factor 1 (IRF-1) in tumor necrosis factor α (TNFα)-induced interleukin-18 binding protein a (IL-18BPa) expression in rheumatoid arthritis synovial fibroblasts (RASFs).

METHODS:

TNFα-induced IRF-1 expression was assessed by real-time quantitative polymerase chain reaction and Western blotting. The effect of TNFα on IRF-1 was assessed using nuclear and cytoplasmic extracts, Western blots, and immunofluorescence. Chemical inhibitors of NF-κB or MAP kinases were used to analyze the signaling pathways of TNFα-induced IRF-1 expression and IRF-1 nuclear translocation. Control and IRF-1 small interfering RNA (siRNA) were used to analyze the effect of IRF-1 down-regulation on TNFα-induced IL-18BP expression. IL-18BPa expression was assessed by enzyme-linked immunosorbent assay, and IL-18 was assessed at the transcription and bioactivity levels using KG-1 cells.

RESULTS:

TNFα induced RASF IRF-1 expression at the messenger RNA and protein levels, with a maximal effect at 2 hours (P < 0.05; n ≥ 3). Furthermore, TNFα induced nuclear translocation of IRF-1, with maximal translocation at 2 hours (∼6 fold-induction) (P < 0.05; n = 4). Blocking of the NF-κB or JNK-2 pathways reduced TNFα-induced IRF-1 nuclear translocation by 35% and 50%, respectively (P < 0.05; n ≥ 4). Using siRNA to knock down IRF-1, we observed reduced IL-18BPa expression. Additionally, IL-18 bioactivity was higher when siRNA was used to knock down IRF-1 expression.

CONCLUSION:

These results show that IRF-1 is a key regulator of IL-18BPa expression and IL-18 bioactivity in RASFs. Regulation of IRF-1 will be a new therapeutic target in RA.

PMID:
21834067
PMCID:
PMC4416229
DOI:
10.1002/art.30583
[Indexed for MEDLINE]
Free PMC Article
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