Tumour necrosis factor alpha-driven IL-32 expression in rheumatoid arthritis synovial tissue amplifies an inflammatory cascade
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SourceAnnals of the Rheumatic Diseases, 70, 4, (2011), pp. 660-667
Article / Letter to editor
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Annals of the Rheumatic Diseases
SubjectN4i 1: Pathogenesis and modulation of inflammation NCMLS 1: Infection and autoimmunity; NCEBP 2: Evaluation of complex medical interventions N4i 4: Auto-immunity, transplantation and immunotherapy; NCMLS 1: Infection and autoimmunity N4i 4: Auto-immunity, transplantation and immunotherapy
OBJECTIVE: To investigate the interplay between IL-32 and tumour necrosis factor alpha (TNFalpha) during the chronic inflammation of rheumatoid arthritis (RA) and to assess whether anti-TNFalpha treatment of RA patients modulates synovial IL-32 expression. METHODS: Induction of IL-32gamma by Pam3Cys, lipopolysaccharide, IL-1beta or TNFalpha was investigated in human fibroblast-like synoviocytes (FLS). Stimulation of TNFalpha production by IL-32gamma was studied by adenoviral overexpression of IL-32gamma (AdIL-32gamma) and lipopolysaccharide stimulation of THP1 cells. Silencing of endogenous IL-32 was employed to study cytokine regulation in FLS. AdIL-32gamma followed by TNFalpha stimulation was performed in FLS to investigate cytokine induction. Immunohistochemistry was applied to study IL-32 expression in synovial biopsies from RA patients. RESULTS: TNFalpha potently induced IL-32gamma expression in FLS. Increased TNFalpha, IL-1beta, IL-6 and CXCL8 production was observed after IL-32gamma overexpression and lipopolysaccharide stimulation of THP1 cells. TNFalpha stimulation of FLS after silencing IL-32gamma resulted in diminished IL-6 and CXCL8 production, whereas IL-32gamma overexpression resulted in enhanced IL-6 and CXCL8 levels. Remarkably, the mechanism through which IL-32gamma overexpression induced TNFalpha, IL-1beta and CXCL8 was by counteracting messenger RNA decay. Importantly, treatment of RA patients with anti-TNFalpha resulted in significant reduction of IL-32 protein in synovial tissue. CONCLUSIONS: TNFalpha is a potent inducer of endogenous IL-32 expression and IL-32 itself contributes to prolonged TNFalpha production, thus inducing an important auto-inflammatory loop. Treatment of RA patients with anti-TNFalpha antibodies diminished IL-32 expression in synovial tissue. The potent anti-inflammatory effect of TNFalpha blockade in RA patients may be partly due to the reduction of synovial IL-32 expression.
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