Article Text

Download PDFPDF
Extended report
The IL1-like cytokine IL33 and its receptor ST2 are abnormally expressed in the affected skin and visceral organs of patients with systemic sclerosis
  1. Mirko Manetti1,2,
  2. Lidia Ibba-Manneschi1,
  3. Vasiliki Liakouli3,
  4. Serena Guiducci2,
  5. Anna Franca Milia2,
  6. Gemma Benelli1,
  7. Alessandra Marrelli3,
  8. Maria Letizia Conforti2,
  9. Eloisa Romano2,
  10. Roberto Giacomelli3,
  11. Marco Matucci-Cerinic2,
  12. Paola Cipriani3
  1. 1Department of Anatomy, Histology and Forensic Medicine, University of Florence, Florence, Italy
  2. 2Department of Biomedicine, Division of Rheumatology, AOUC, and Excellence Centre for Research, Transfer and High Education DENOthe, University of Florence, Florence, Italy
  3. 3Department of Internal Medicine and Public Health, Division of Rheumatology, University of L’Aquila, L’Aquila, Italy
  1. Correspondence to Professor L Ibba-Manneschi, Department of Anatomy, Histology and Forensic Medicine, University of Florence, Viale G B Morgagni 85, 50134 Florence, Italy; ibba{at}


Background Early endothelial cell (EC) activation/damage and profibrotic Th2-associated cytokines play a pivotal role in systemic sclerosis (SSc). Interleukin 33 (IL33) is a novel member of the IL1 family that promotes Th2 responses and inflammation through the ST2 receptor. IL33 is also a chromatin-associated transcriptional regulator in ECs.

Objective To investigate the role of the IL33/ST2 axis in SSc.

Methods Skin biopsies were obtained from 30 patients with SSc (15 early/15 late stage) and 10 healthy subjects. Lung, kidney, heart, oesophagus, stomach, placenta biopsies and bronchoalveolar lavage cells from patients with SSc and controls were also analysed. IL33/ST2 expression was investigated by immunohistology, confocal immunofluorescence microscopy, western blotting and RT-PCR.

Results In skin biopsies from control subjects, constitutive nuclear IL33 protein expression was found in dermal ECs and keratinocytes, while ST2 was weakly expressed in ECs and fibroblasts. In skin biopsies from patients with early SSc, IL33 protein was downregulated or absent in ECs and epidermis while IL33 mRNA was normally expressed or even upregulated. Moreover, ECs, perivascular infiltrating mast cells, CD68-positive macrophages, CD3-positive T cells, CD20-positive B cells and activated fibroblasts/myofibroblasts exhibited strong ST2 expression. In skin biopsies from patients with late SSc, IL33 was constitutively found in most ECs while ST2 immunostaining was weaker. In early SSc, the loss of endothelial IL33 protein and the overexpression of ST2 involved all affected organs. Dermal and pulmonary fibroblasts showed IL33 expression in SSc.

Conclusion IL33 and ST2 are abnormally expressed in SSc. In early SSc, upon EC activation/damage IL33 may be mobilised from ECs to signal through ST2 in key profibrotic players such as inflammatory/immune cells and fibroblasts/myofibroblasts.

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.


  • Funding This study was supported by grants from the Ministero dell'Istruzione, dell'Università e della Ricerca (MIUR), the University of Florence (ex60%) and the Associazione per lo studio della Sclerosi Sistemica e delle Malattie Fibrosanti (ASSMaF onlus).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval The study was approved by the Institutional Review Board.

  • Provenance and peer review Not commissioned; externally peer reviewed.