| Systemic sclerosis Th2 cells inhibit collagen production by dermal fibroblasts via membrane-associated tumor necrosis factor alpha. | |
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MedLine Citation:
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PMID: 13130479 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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OBJECTIVE: In systemic sclerosis (SSc; scleroderma), T cells infiltrate organs undergoing fibrotic changes and may participate in dysregulated production of collagen by fibroblasts. The objective of this study was to functionally characterize T cells infiltrating skin lesions in early SSc and investigate their capacity to affect production of type I collagen and interstitial collagenase (matrix metalloproteinase 1 [MMP-1]) by dermal fibroblasts. METHODS: Four-color cytometric analysis was used to characterize subset distribution and production of interferon-gamma (IFN gamma) and interleukin-4 (IL-4) in T cell lines generated from the skin of patients with SSc. T cell clones were generated, and their capacity to modulate collagen and MMP-1 production by fibroblasts derived from patients with SSc and from normal individuals was assessed. Neutralizing reagents were used to identify T cell mediators involved in fibroblast modulation. RESULTS: The skin of individuals with early-stage SSc contained T cells preferentially producing high levels of IL-4. Cloned CD4+ Th2-like cells inhibited collagen production by normal fibroblasts. Th2 cell-dependent inhibition was, at least in part, contact-dependent, was essentially mediated by tumor necrosis factor alpha (TNF alpha), and was dominant over the enhancement induced by profibrotic IL-4 and transforming growth factor beta cytokines. The simultaneous induction of MMP-1 production confirmed the specificity of these observations. To be inhibitory, Th2 cells required activation by CD3 ligation. Th2 cells were less potent than were Th1 cells in inhibiting collagen production by normal fibroblasts via cell-to-cell interaction, and SSc fibroblasts were resistant to inhibition. CONCLUSION: These findings indicate that, despite their production of IL-4, Th2 cells reduce type I collagen synthesis by dermal fibroblasts because of the dominant effect of TNF alpha, and suggest that strategies based on TNF alpha blockade aimed at controlling fibrosis in SSc may be unwise. |
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Authors:
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Carlo Chizzolini; Yann Parel; Carmelina De Luca; Alan Tyndall; Anita Akesson; Agneta Scheja; Jean-Michel Dayer |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Arthritis and rheumatism Volume: 48 ISSN: 0004-3591 ISO Abbreviation: Arthritis Rheum. Publication Date: 2003 Sep |
Date Detail:
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Created Date: 2003-09-17 Completed Date: 2003-10-17 Revised Date: 2008-11-21 |
Medline Journal Info:
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Nlm Unique ID: 0370605 Medline TA: Arthritis Rheum Country: United States |
Other Details:
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Languages: eng Pagination: 2593-604 Citation Subset: AIM; IM |
Affiliation:
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Division of Immunologya and Allergy, Geneva University Hospital, Geneva, Switzerland. chizzolini@medecine.unige.ch |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adult Cell Communication / immunology Cell Line Cell Membrane / immunology, metabolism Collagen / genetics, metabolism* Dermis / cytology, immunology, metabolism Female Fibroblasts / cytology, immunology, metabolism* Gene Expression / immunology Humans Interferon-gamma / biosynthesis Interleukin-4 / biosynthesis Male Matrix Metalloproteinase 1 / genetics, metabolism Middle Aged RNA, Messenger / analysis Scleroderma, Systemic / immunology*, metabolism* T-Lymphocyte Subsets / cytology, immunology Th2 Cells / cytology, immunology*, metabolism Tumor Necrosis Factor-alpha / immunology, metabolism* |
| Chemical | |
Reg. No./Substance:
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0/RNA, Messenger; 0/Tumor Necrosis Factor-alpha; 207137-56-2/Interleukin-4; 82115-62-6/Interferon-gamma; 9007-34-5/Collagen; EC 3.4.24.7/Matrix Metalloproteinase 1 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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