Objective During the course of rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) are chronically exposed to an inflammatory milieu. In the current study we test the hypothesis that chronic exposure of FLS to TNFα augments inflammatory responses to secondary stimuli (priming effect). Methods FLS obtained from RA patients were chronically exposed to TNFα (3 days) and then were stimulated with interferons (IFNs). Expression of IFN-target genes was measured by real-time quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. Total STAT1 protein and IFN-mediated STAT1 activation were evaluated by Western blotting. Total histone levels, histone acetylation, NF-κB p65 and RNA polymerase II (pol II) recruitment were measured at the promoter of CXCL10 (encodes 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/MIG and CXCL11/ITAC production upon subsequent IFN stimulation. This phenotype was retained over a period of days even after the removal of TNFα. Prolonged TNFα 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 STAT1 led to amplification of IFN-induced STAT1 activation. Conclusions 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 priming of chromatin, sustained activation of NF-κB, and amplification of STAT1 activation downstream of IFNs. These data also suggest that FLS gain an “inflammatory memory” upon chronic exposure to TNFα.

During rheumatoid arthritis (RA), Tumor Necrosis Factor (TNF) activates fibroblast-like synoviocytes (FLS) inducing in a temporal order a constellation of genes, which perpetuate synovial inflammation. Although the molecular mechanisms regulating TNF-induced transcription are well characterized, little is known about the impact of mRNA stability on gene expression and the impact of TNF on decay rates of mRNA transcripts in FLS. To address these issues we performed RNA sequencing and genome-wide analysis of the mRNA stabilome in RA FLS. We found that TNF induces a biphasic gene expression program: initially, the inducible transcriptome consists primarily of unstable transcripts but progressively switches and becomes dominated by very stable transcripts. This temporal switch is due to: a) TNF-induced prolonged stabilization of previously unstable transcripts that enables progressive transcript accumulation over days and b) sustained expression and late induction of very stable transcripts. TNF-induced mRNA stabilization in RA FLS occurs during the late phase of TNF response, is MAPK-dependent, and involves several genes with pathogenic potential such as IL6, CXCL1, CXCL3, CXCL8/IL8, CCL2, and PTGS2. These results provide the first insights into genome-wide regulation of mRNA stability in RA FLS and highlight the potential contribution of dynamic regulation of the mRNA stabilome by TNF to chronic synovitis.

Extraadrenal paragangliomas involving the spine is less common and usually takes the form of intradural compression of the cauda equina. The authors report three cases of spinal paragangliomas resulting in extradural spinal cord compression and their MR findings. The MR imaging revealed a well-demarcated extradural mass with low to intermediate signal intensity on T1-weighted images and intermediate to high signal intensity on T2-weighted images compared to paravertebral muscles. After Gd-DTPA administration, heterogeneous and intense enhancement was found. Multiple punctate and serpiginous structures of signal void due to high-velocity flow were noted around and within the tumors on all sequences. In one case, the signal void structures were well corresponded with feeding arteries on angiography. These may be the characteristic findings of the extraadrenal paraganglioma involving the spine.

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The outcome of patients with DILI was poor. MELD score and Hb were reliable predictors of short-term outcome in patients with DILI.