High IL-17E and low IL-17C dermal expression identifies a fibrosis-specific motif common to morphea and systemic sclerosis

PLoS One. 2014 Aug 19;9(8):e105008. doi: 10.1371/journal.pone.0105008. eCollection 2014.

Abstract

Background: High interleukin (IL)-17A levels are characteristically found in the skin of systemic sclerosis (SSc) individuals. Our aim was to investigate whether the dermal expression of IL-17A and related IL-17 family members (i.e. IL-17C, IL-17E and IL-17F) could distinguish fibrotic from healthy skin and could show similarities in SSc and morphea, two disorders with presumed distinct pathogenesis, but characterized by skin fibrosis.

Methods: Biopsies were obtained from the involved skin of 14 SSc, 5 morphea and 8 healthy donors (HD) undergoing plastic surgery. Immunohistochemistry/immunofluorescence techniques were coupled to a semi-automated imaging quantification approach to determine the presence of the IL-17 family members in the skin. The in vitro effects induced by the IL-17 family members on fibroblasts from normal and SSc individuals were assessed by ELISA and RIA.

Results: Positive cells for each of the IL-17 isoforms investigated were present in the dermis of all the individuals tested, though with variable frequencies. SSc individuals had increased frequency of IL-17A+ (p = 0.0237) and decreased frequency of IL-17F+ (p = 0.0127) and IL-17C+ cells (p = 0.0008) when compared to HD. Similarly, morphea individuals had less frequent IL-17C+ cells (p = 0.0186) in their skin but showed similar number of IL-17A+ and IL-17F+ cells when compared to HD. Finally, IL-17E+ cells were more numerous in morphea (p = 0.0109) and tended to be more frequent in SSc than in HD. Fibroblast production of IL-6, MMP-1 and MCP-1 was enhanced in a dose-dependent manner in the presence of IL-17E and IL-17F, but not in the presence of IL-17C. None of the cytokine tested had significant effect on type I collagen production. Of interest, in SSc the frequency of both IL-17A and IL-17F positive cells increased with disease duration.

Conclusions: The frequency of IL-17A and IL-17F distinguish SSc to morphea individuals while dermal expression of IL-17C (low) and IL-17E (high) identifies a fibrosis-specific motif. The specific IL-17C/IL-17E cytokine combination may thus play a role in the development of fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Biomarkers / metabolism
  • Case-Control Studies
  • Cells, Cultured
  • Dermis / metabolism*
  • Dermis / pathology
  • Female
  • Fibroblasts / metabolism
  • Fibrosis
  • Humans
  • Interleukin-17 / metabolism*
  • Male
  • Middle Aged
  • Prospective Studies
  • Scleroderma, Localized / metabolism*
  • Scleroderma, Localized / pathology
  • Scleroderma, Systemic / metabolism*
  • Scleroderma, Systemic / pathology
  • Young Adult

Substances

  • Biomarkers
  • IL25 protein, human
  • Interleukin-17

Grant support

Work supported in part by grant 310030_140791 from the Swiss National Science Foundation and the Hans Wilsdorf foundation to CC. PL and PLM were supported by a grant from Ricerca Corrente IRCCS Istituto Auxologico Italiano, Italy. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.