Our data demonstrate that priming of human neutrophils with TNF-α promotes uric acid-mediated IL-1β secretion in the absence of microbial stimulation. These findings provide insights into the neutrophils-mediated inflammatory processes in gouty arthritis.
Background
Anti-citrullinated peptide antibodies (ACPA) and inflammatory cytokines play important roles in the development of rheumatoid arthritis (RA). T cell immunoglobulin and mucin–domain containing–3 (TIM–3) is an immune-checkpoint molecule involved in inhibitory signaling. Galectin–9 (Gal–9) mediated ligation of TIM–3 induces the amelioration of autoimmune diseases. TIM–3 is expressed in synovial osteoclasts and involved in the rheumatoid bone destruction. The aim of this study was to investigate the relationships between inflammatory cytokines and immune–checkpoint molecules in RA patients.
Methods
Serum levels of interleukin–6 (IL–6), tumor necrosis factor–α (TNF–α), soluble TIM–3 (sTIM–3) and Gal–9 were determined by ELISA. Patients were stratified into two groups based on ACPA titers: low-medium ACPA (ACPA <200 U/mL) and high ACPA (ACPA ≥200 U/mL). Serum levels of cytokines or immune-checkpoint molecules were evaluated between RA patients with low-medium ACPA titers and high ACPA titers.
Results
Elevated serum levels of inflammatory cytokines were correlated with DAS28–ESR in RA patients. Although serum levels of sTIM–3 were elevated in RA patients, significant correlations between sTIM–3 and cytokines (IL–6 or TNF–α) were observed exclusively in RA patients with low-medium ACPA titers (<200 U/mL). Serum levels of IL–6 and TNF–α levels were significantly correlated with elevated Gal–9 levels regardless of ACPA status. A significant correlation between IL–6 and Gal–9 was observed in RA patients without advanced joint damage. Conversely, a significant correlation between TNF–α and Gal–9 was observed in RA patients with advanced joint damage.
Conclusions
Our data indicated that there are positive correlations between circulating inflammatory cytokines and checkpoint molecules in RA patients and these interactions can be modulated by ACPA status or joint damage stage.
Background
The efficacy of tocilizumab (TCZ) in the treatment of Takayasu arteritis (TA) was demonstrated in randomized controlled trials. The objective of this study was to analyze the effectiveness of combining TCZ with glucocorticoids (GC) as induction therapy in patients with TA.
Method
This was a retrospective observational study including 32 patients with newly-diagnosed TA. Clinical effectiveness of TCZ in maintaining relapse-free remission and GC-tapering were compared between patients who were treated with TCZ plus GC and those who were treated with GC with or without immunosuppressants.
Results
The study comprised 32 patients (27 women/5 men) with a median age of 25.5 years (range, 13–72). In the TCZ group (n = 14), patients received TCZ in combination with GC as an induction therapy. In the non-TCZ group (n = 18), patients were treated with single-agent GC or GC plus immunosuppressant. In the matched analysis, relapse-free survival rate was significantly higher in the TCZ group as compared to the non-TCZ group during GC taper.
Conclusion
TCZ, in combination with GC, would be an effective alternative induction regimen for patients with TA.
Objective
Interferon-gamma (IFN-γ) is overexpressed in rheumatoid synovium and thought to be involved in the pathogenesis of rheumatoid arthritis (RA). In this study, we examined our hypothesis that IFN-γ activates innate immune cells and upregulates inflammatory cytokines. Peripheral blood neutrophils were stimulated with IFN-γ in the presence or absence of Janus kinase (JAK) inhibitors. Interleukin-6 (IL-6) mRNA and protein expression were analyzed using real-time polymerase chain reaction (PCR) method and enzyme-linked immunosorbent assay. Protein phosphorylation of JAKs or STAT1 was assessed by Western blot using phospho-specific antibodies.
Results
IFN-γ stimulation induces IL-6 expression in protein and mRNA levels in human neutrophils. Furthermore, IFN-γ stimulation induces JAK1/JAK2 phosphorylation and downstream signal transducer and activator of transcription (STAT) 1 phosphorylation in human neutrophils. Although all JAKi, blocked IFN-γ-induced JAK1.2/STAT1 phosphorylation at higher concentrations (100 nM), baricitinib most efficiently inhibited IFN-γ-induced JAK1.2/STAT1 phosphorylation at lower concentrations (≤ 25 nM). Among these JAKi, baricitinib was the most potent regulator for IFN-γ-induced IL-6 production in human neutrophils. Our data indicate that IFN-γ upregulates IL-6 production via the JAK1/2-STAT1 pathway in human innate immune cells. Furthermore, this IFN-γ-mediated IL-6 induction via JAK/STAT was downregulated by JAKi.
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