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Systemic sclerosis Th2 cells inhibit collagen production by dermal fibroblasts via membrane-associated tumor necrosis factor alpha

Chizzolini, C ; Parel, Y ; De Luca, C ; Tyndall, A ; Åkesson, Anita LU ; Scheja, Agneta LU and Dayer, JM (2003) In Arthritis and Rheumatism 48(9). p.2593-2604
Abstract
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 (IFNgamma) 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... (More)
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 (IFNgamma) 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 (TNFalpha), 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 TNFalpha, and suggest that strategies based on TNFalpha blockade aimed at controlling fibrosis in SSc may be unwise. (Less)
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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Arthritis and Rheumatism
volume
48
issue
9
pages
2593 - 2604
publisher
John Wiley & Sons Inc.
external identifiers
  • wos:000185431900024
  • pmid:13130479
  • scopus:0141564934
ISSN
1529-0131
DOI
10.1002/art.11129
language
English
LU publication?
yes
id
5a9bc8ea-22f4-4e69-9597-171363b42681 (old id 300683)
date added to LUP
2016-04-01 11:34:51
date last changed
2022-01-26 07:15:08
@article{5a9bc8ea-22f4-4e69-9597-171363b42681,
  abstract     = {{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 (IFNgamma) 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 (TNFalpha), 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 TNFalpha, and suggest that strategies based on TNFalpha blockade aimed at controlling fibrosis in SSc may be unwise.}},
  author       = {{Chizzolini, C and Parel, Y and De Luca, C and Tyndall, A and Åkesson, Anita and Scheja, Agneta and Dayer, JM}},
  issn         = {{1529-0131}},
  language     = {{eng}},
  number       = {{9}},
  pages        = {{2593--2604}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Arthritis and Rheumatism}},
  title        = {{Systemic sclerosis Th2 cells inhibit collagen production by dermal fibroblasts via membrane-associated tumor necrosis factor alpha}},
  url          = {{http://dx.doi.org/10.1002/art.11129}},
  doi          = {{10.1002/art.11129}},
  volume       = {{48}},
  year         = {{2003}},
}