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Prolonged tumor necrosis factor α primes fibroblast-like synoviocytes in a gene-specific manner by altering chromatin. | LitMetric

AI Article Synopsis

Article Abstract

Objective: 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).

Methods: 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 CXCL10 promoter (encodes IFNγ-inducible 10-kd protein [IP-10]) by chromatin immunoprecipitation assays.

Results: 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 CXCL10 promoter. In parallel, an increase in intracellular STAT-1 led to amplification of IFN-induced STAT-1 activation.

Conclusion: 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4455921PMC
http://dx.doi.org/10.1002/art.38871DOI Listing

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