Prolonged Tumor Necrosis Factor α Primes Fibroblast‐like Synoviocytes in a Gene‐Specific Manner by Altering Chromatin. Issue 1 (January 2015)

• Record Type: Journal Article
• Authors: Sohn, Christopher; Lee, Angela; Qiao, Yu; Loupasakis, Konstantinos; Ivashkiv, Lionel B.; Kalliolias, George D.
• Is Part Of: Arthritis & rheumatology. Volume 67:Issue 1(2015)
• Page Start: 86
• Page End: 95
• Publication Date: 2015-01
• Subjects: Arthritis -- Periodicals; Rheumatism -- Periodicals; 616.72
• DOI: 10.1002/art.38871
• Languages: English
• ISSNs: 2326-5191

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="art38871-sec-0001" sec-type="section"> <title>Objective</title> <p>During the course of rheumatoid arthritis (RA), fibroblast‐like synoviocytes (FLS) are chronically exposed to an inflammatory milieu. The purpose of this study was to test the hypothesis that prolonged exposure of FLS to tumor necrosis factor α (TNFα) augments inflammatory responses to secondary stimuli (priming effect).</p> </sec> <sec id="art38871-sec-0002" sec-type="section"> <title>Methods</title> <p>FLS obtained from RA patients were exposed to TNFα for 3 days and were then stimulated with interferons (IFNs). Expression of IFN target genes was measured by real‐time quantitative reverse transcription–polymerase chain reaction analysis and enzyme‐linked immunosorbent assay. Total STAT‐1 protein and IFN‐mediated STAT‐1 activation were evaluated by Western blotting. Total histone levels, histone acetylation, and NF‐κB p65 and RNA polymerase II (Pol II) recruitment were measured at the <italic>CXCL10</italic> promoter (encodes IFNγ‐inducible 10‐kd protein [IP‐10]) by chromatin immunoprecipitation assays.</p> </sec> <sec id="art38871-sec-0003" sec-type="section"> <title>Results</title> <p>Prolonged pre‐exposure of FLS to TNFα enhanced the magnitude and extended the kinetics of CXCL10/IP‐10, CXCL9, and CXCL11 production upon subsequent IFN stimulation. This phenotype was retained over a period of days, even after the removal of TNFα. Prolonged TNFα exposure decreased histone levels, increased acetylation of the remaining histones, and heightened recruitment of NF‐κB p65 and Pol II to the <italic>CXCL10</italic> promoter. In parallel, an increase in intracellular STAT‐1 led to amplification of IFN‐induced STAT‐1 activation.</p> </sec> <sec id="art38871-sec-0004" sec-type="section"> <title>Conclusion</title> <p>Our study reveals a novel pathogenic function of TNFα, namely, prolonged and gene‐specific priming of FLS for enhanced transcription of inflammatory chemokine genes due to the priming of chromatin, the sustained activation of NF‐κB, and the amplification of STAT‐1 activation downstream of IFNs. These data also suggest that FLS gain an "inflammatory memory" upon prolonged exposure to TNFα.</p> </sec> </abstract>