Takashi Taniguchi1,2, Yoshihide Asano3,4, Kouki Nakamura1,2, Takashi Yamashita1,2, Ryosuke Saigusa1,2, Yohei Ichimura1,2, Takehiro Takahashi1,2, Tetsuo Toyama1,2, Ayumi Yoshizaki1,2, Shinichi Sato1,2. 1. From the Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan. 2. T. Taniguchi, MD, PhD, Assistant Professor, Department of Dermatology, University of Tokyo Graduate School of Medicine; Y. Asano, MD, PhD, Associate Professor, Department of Dermatology, University of Tokyo Graduate School of Medicine; K. Nakamura, MD, Graduate Student, Department of Dermatology, University of Tokyo Graduate School of Medicine; T. Yamashita, MD, Graduate Student, Department of Dermatology, University of Tokyo Graduate School of Medicine; R. Saigusa, MD, Graduate Student, Department of Dermatology, University of Tokyo Graduate School of Medicine; Y. Ichimura, MD, PhD, Assistant Professor, Department of Dermatology, University of Tokyo Graduate School of Medicine; T. Takahashi, MD, PhD, Assistant Professor, Department of Dermatology, University of Tokyo Graduate School of Medicine; T. Toyama, MD, PhD, Assistant Professor, Department of Dermatology, University of Tokyo Graduate School of Medicine; A. Yoshizaki, MD, PhD, Lecturer, Department of Dermatology, University of Tokyo Graduate School of Medicine; S. Sato, MD, PhD, Professor, Department of Dermatology, University of Tokyo Graduate School of Medicine. 3. From the Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan. yasano-tky@umin.ac.jp. 4. T. Taniguchi, MD, PhD, Assistant Professor, Department of Dermatology, University of Tokyo Graduate School of Medicine; Y. Asano, MD, PhD, Associate Professor, Department of Dermatology, University of Tokyo Graduate School of Medicine; K. Nakamura, MD, Graduate Student, Department of Dermatology, University of Tokyo Graduate School of Medicine; T. Yamashita, MD, Graduate Student, Department of Dermatology, University of Tokyo Graduate School of Medicine; R. Saigusa, MD, Graduate Student, Department of Dermatology, University of Tokyo Graduate School of Medicine; Y. Ichimura, MD, PhD, Assistant Professor, Department of Dermatology, University of Tokyo Graduate School of Medicine; T. Takahashi, MD, PhD, Assistant Professor, Department of Dermatology, University of Tokyo Graduate School of Medicine; T. Toyama, MD, PhD, Assistant Professor, Department of Dermatology, University of Tokyo Graduate School of Medicine; A. Yoshizaki, MD, PhD, Lecturer, Department of Dermatology, University of Tokyo Graduate School of Medicine; S. Sato, MD, PhD, Professor, Department of Dermatology, University of Tokyo Graduate School of Medicine. yasano-tky@umin.ac.jp.
Abstract
OBJECTIVE: CXCL6, a chemokine with proangiogenic property, is reported to be involved in vasculopathy associated with systemic sclerosis (SSc). We investigated the contribution of CXCL6 to SSc development by focusing on the association of friend leukemia virus integration 1 (Fli1) deficiency, a potential predisposing factor of SSc, with CXCL6 expression and clinical correlation of serum CXCL6 levels. METHODS: mRNA levels of target genes and the binding of Fli1 to the CXCL6 promoter were evaluated by quantitative reverse transcription-PCR and chromatin immunoprecipitation, respectively. Serum CXCL6 levels were determined by ELISA. RESULTS: FLI1 siRNA significantly enhanced CXCL6 mRNA expression in human dermal fibroblasts and human dermal microvascular endothelial cells, while Fli1 haploinsufficiency significantly suppressed CXCL6 mRNA expression in murine peritoneal macrophages stimulated with lipopolysaccharide. Supporting a critical role of Fli1 deficiency to induce SSc-like phenotypes, CXCL6 mRNA expression was higher in SSc dermal fibroblasts than in normal dermal fibroblasts. Importantly, Fli1 bound to the CXCL6 promoter in dermal fibroblasts, endothelial cells, and THP-1 cells. In patients with SSc, serum CXCL6 levels correlated positively with the severity of dermal and pulmonary fibrosis and were elevated in association with cardiac and pulmonary vascular involvement and cutaneous vascular symptoms, including Raynaud phenomenon, digital ulcers (DU)/pitting scars, and telangiectasia. Especially, serum CXCL6 levels were associated with DU/pitting scars and heart involvement by multiple regression analysis. CONCLUSION: CXCL6 expression is upregulated by Fli1 deficiency in fibroblasts and endothelial cells, potentially contributing to the development of fibrosis and vasculopathy in the skin, lung, and heart of SSc.
OBJECTIVE:CXCL6, a chemokine with proangiogenic property, is reported to be involved in vasculopathy associated with systemic sclerosis (SSc). We investigated the contribution of CXCL6 to SSc development by focusing on the association of friend leukemia virus integration 1 (Fli1) deficiency, a potential predisposing factor of SSc, with CXCL6 expression and clinical correlation of serum CXCL6 levels. METHODS: mRNA levels of target genes and the binding of Fli1 to the CXCL6 promoter were evaluated by quantitative reverse transcription-PCR and chromatin immunoprecipitation, respectively. Serum CXCL6 levels were determined by ELISA. RESULTS:FLI1 siRNA significantly enhanced CXCL6 mRNA expression in human dermal fibroblasts and human dermal microvascular endothelial cells, while Fli1haploinsufficiency significantly suppressed CXCL6 mRNA expression in murine peritoneal macrophages stimulated with lipopolysaccharide. Supporting a critical role of Fli1 deficiency to induce SSc-like phenotypes, CXCL6 mRNA expression was higher in SSc dermal fibroblasts than in normal dermal fibroblasts. Importantly, Fli1 bound to the CXCL6 promoter in dermal fibroblasts, endothelial cells, and THP-1 cells. In patients with SSc, serum CXCL6 levels correlated positively with the severity of dermal and pulmonary fibrosis and were elevated in association with cardiac and pulmonary vascular involvement and cutaneous vascular symptoms, including Raynaud phenomenon, digital ulcers (DU)/pitting scars, and telangiectasia. Especially, serum CXCL6 levels were associated with DU/pitting scars and heart involvement by multiple regression analysis. CONCLUSION:CXCL6 expression is upregulated by Fli1 deficiency in fibroblasts and endothelial cells, potentially contributing to the development of fibrosis and vasculopathy in the skin, lung, and heart of SSc.
Authors: Tom Gyllenhammar; Mikael Kanski; Henrik Engblom; Dirk M Wuttge; Marcus Carlsson; Roger Hesselstrand; Håkan Arheden Journal: BMC Cardiovasc Disord Date: 2018-01-30 Impact factor: 2.298