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The IL-1-like cytokine IL-33 and its receptor ST2 are abnormally expressed in the affected skin and visceral organs of patients with systemic sclerosis
  1. Mirko Manetti (mirkomanetti{at}yahoo.it)
  1. Department of Anatomy, Histology and Forensic Medicine, University of Florence, Florence, Italy
    1. Lidia Ibba-Manneschi (ibba{at}unifi.it)
    1. Department of Anatomy, Histology and Forensic Medicine, University of Florence, Florence, Italy
      1. Vasiliki Liakouli (vasiliki_liakouli{at}yahoo.it)
      1. Department of Internal Medicine and Public Health, Division of Rheumatology, University of L’Aquila, Italy
        1. Serena Guiducci (serena16{at}libero.it)
        1. Department of Biomedicine, Division of Rheumatology, AOUC, University of Florence, Florence, Italy
          1. Anna Franca Milia (milia_af{at}yahoo.it)
          1. Department of Biomedicine, Division of Rheumatology, AOUC, University of Florence, Florence, Italy
            1. Gemma Benelli (gebenelli{at}gmail.com)
            1. Department of Anatomy, Histology and Forensic Medicine, University of Florence, Florence, Italy
              1. Alessandra Marrelli (alessandramarrelli{at}tiscalinet.it)
              1. Department of Internal Medicine and Public Health, Division of Rheumatology, University of L’Aquila, Italy
                1. Maria Letizia Conforti (mletiziaconforti{at}hotmail.it)
                1. Department of Biomedicine, Division of Rheumatology, AOUC, University of Florence, Florence, Italy
                  1. Eloisa Romano (eloisaromano{at}libero.it)
                  1. Department of Biomedicine, Division of Rheumatology, AOUC, University of Florence, Florence, Italy
                    1. Roberto Giacomelli (roberto.giacomelli{at}cc.univaq.it)
                    1. Department of Internal Medicine and Public Health, Division of Rheumatology, University of L’Aquila, Italy
                      1. Marco Matucci-Cerinic (cerinic{at}unifi.it)
                      1. Department of Biomedicine, Division of Rheumatology, AOUC, University of Florence, Florence, Italy
                        1. Paola Cipriani (paola.cipriani{at}cc.univaq.it)
                        1. Department of Internal Medicine and Public Health, Division of Rheumatology, University of L’Aquila, Italy

                          Abstract

                          Background: Early endothelial cell (EC) activation/damage and pro-fibrotic Th2-associated cytokines play a pivotal role in systemic sclerosis (SSc). Interleukin (IL)-33 is a novel IL-1 family member that promotes Th2-responses and inflammation through the ST2 receptor. IL-33 is also a chromatin-associated transcriptional regulator in ECs.

                          Objective: To investigate the role of IL-33/ST2 axis in SSc.

                          Methods: Skin biopsies were obtained from 30 SSc patients (15 early/15 late stage) and 10 healthy subjects. Lung, kidney, heart, esophagus, stomach, placenta biopsies and bronchoalveolar lavage cells from SSc patients and controls were also analysed. IL-33/ST2 expression was investigated by immunohistology, confocal immunofluorescence microscopy, Western blotting and RT-PCR.

                          Results: In control skin, constitutive nuclear IL-33 protein expression was found in dermal ECs and keratinocytes, while ST2 was weakly expressed in ECs and fibroblasts. In early SSc skin, IL-33 protein was down-regulated or absent in ECs and epidermis, while IL-33 mRNA was normally expressed or even up-regulated. 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 late SSc skin, IL-33 was constitutively found in most ECs, while ST2 immunostaining was weaker. In early SSc, the loss of endothelial IL-33 protein and the overexpression of ST2 involved all affected organs. Dermal and pulmonary fibroblasts showed IL-33 expression in SSc.

                          Conclusion: IL-33 and ST2 are abnormally expressed in SSc. In early SSc, upon EC activation/damage, IL-33 may be mobilised from ECs to signal through ST2 in key pro-fibrotic players, such as inflammatory/immune cells and fibroblasts/myofibroblasts.

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