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Tumor necrosis factor co-stimulated T-lymphocytes from patients with systemic sclerosis trigger collagen production in fibroblasts.
MedLine Citation:
PMID:  23045159     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
OBJECTIVE.: The role of tumor necrosis factor (TNF) in Systemic Sclerosis (SSc) remains controversial. We aimed to investigate the influence of TNF receptor (TNFR) co-stimulated lymphocytes on collagen expression in fibroblasts. METHODS.: TNFR expression on mononuclear cells from dermis and blood of SSc patients was assessed by flow cytometry. Peripheral blood CD3(+) lymphocytes were activated with CD3/28 beads and co-stimulated with TNFR selective variants. IL-6, soluble IL-6 receptor (sIL-6R), IL-10 and IL-13 expression was detected by ELISA or qRT-PCR. Healthy fibroblasts were incubated with conditioned media from TNFR co-stimulated T-lymphocytes and type-1 collagen expression quantified. RESULTS.: TNFR1 and 2 were upregulated on dermal T-lymphocytes of patients with diffuse SSc. TNFR2 expression correlated with skin thickening. After CD3/28 activation, peripheral blood lymphocytes of SSc patients produced more IL-6, sIL-6R and IL-13 compared to healthy lymphocytes. Co-stimulation with TNFR1-selective ligands and soluble TNF further increased IL-6 expression whereas stimulation of TNFR2 led to a higher release of sIL-6R. IL-10 expression, normally occurring after TNFR2 co-stimulation, was impaired in SSc T-cells. Supernatants of TNF co-stimulated SSc lymphocytes induced higher type-1 collagen expression in fibroblasts, which was partially reversible by dual inhibition of IL-6 and IL-13. TNFR and IL-6 expression in the dermis was reversible in a patient after lymphoablative therapy prior to autologous haematopoietic stem cell transplantation. CONCLUSION.: TNF co-stimulated T-lymphocytes from SSc patients have a propensity to secrete profibrotic cytokines, at the expense of IL-10. Therefore, T-lymphocytes in SSc support fibrosis, but might lack capacity to resolve inflammation. © 2012 American College of Rheumatology.
Authors:
Thomas Hügle; Steven O'Reilly; Rachel Simpson; Marina D Kraaij; Venetia Bigley; Matthew Collin; Anja Krippner-Heidenreich; Jacob M van Laar
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-10-8
Journal Detail:
Title:  Arthritis and rheumatism     Volume:  -     ISSN:  1529-0131     ISO Abbreviation:  Arthritis Rheum.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-9     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0370605     Medline TA:  Arthritis Rheum     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 by the American College of Rheumatology.
Affiliation:
Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, United Kingdom; Department of Rheumatology, University Hospital Basel, Switzerland. Huegle@unibas.ch.
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