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

Mirko Manetti ¹, Lidia Ibba-Manneschi ^1*, Vasiliki Liakouli ², Serena Guiducci ³, Anna Franca Milia ³, Gemma Benelli ¹, Alessandra Marrelli ², Maria Letizia Conforti ³, Eloisa Romano ³, Roberto Giacomelli ², Marco Matucci-Cerinic ³ and Paola Cipriani ²

¹ Department of Anatomy, Histology and Forensic Medicine, University of Florence, Florence, Italy
² Department of Internal Medicine and Public Health, Division of Rheumatology, University of L’Aquila, Italy
³ Department of Biomedicine, Division of Rheumatology, AOUC, University of Florence, Florence, Italy

^* To whom correspondence should be addressed. E-mail: ibba{at}unifi.it.

Accepted 17 September 2009

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.