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

Arthritis Rheum. 2003 Sep;48(9):2593-604. doi: 10.1002/art.11129.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cell Communication / immunology
  • Cell Line
  • Cell Membrane / immunology
  • Cell Membrane / metabolism
  • Collagen / genetics
  • Collagen / metabolism*
  • Dermis / cytology
  • Dermis / immunology
  • Dermis / metabolism
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / immunology
  • Fibroblasts / metabolism*
  • Gene Expression / immunology
  • Humans
  • Interferon-gamma / biosynthesis
  • Interleukin-4 / biosynthesis
  • Male
  • Matrix Metalloproteinase 1 / genetics
  • Matrix Metalloproteinase 1 / metabolism
  • Middle Aged
  • RNA, Messenger / analysis
  • Scleroderma, Systemic / immunology*
  • Scleroderma, Systemic / metabolism*
  • T-Lymphocyte Subsets / cytology
  • T-Lymphocyte Subsets / immunology
  • Th2 Cells / cytology
  • Th2 Cells / immunology*
  • Th2 Cells / metabolism
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / metabolism*


  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Interleukin-4
  • Interferon-gamma
  • Collagen
  • Matrix Metalloproteinase 1