The Contribution of LIGHT (TNFSF14) to the Development of Systemic Sclerosis by Modulating IL-6 and T Helper Type 1 Chemokine Expression in Dermal Fibroblasts.

Abstract

Systemic sclerosis (SSc) is an autoimmune and vascular disease resulting in multiple organ fibrosis, in which IL-6 and T helper (Th)2/Th17 cytokines serve as critical disease drivers. LIGHT is a proinflammatory cytokine promoting IL-6 production in lung fibroblasts and Th1 chemokine expression in dermal fibroblasts (DFs) stimulated with IFN-γ. In this study, we investigated the potential contribution of LIGHT to SSc development using clinical samples and animal models. In SSc-involved skin, LIGHT was upregulated in inflammatory cells, whereas herpesvirus entry mediator (HVEM), a receptor of LIGHT, was downregulated in DFs. Similar expression profiles of LIGHT and HVEM were reproduced in bleomycin-treated mice. Transcription factor FLI1 bound to the HVEM promoter, and FLI1 small interfering RNA suppressed HVEM expression in normal DFs. In SSc DFs, LIGHT significantly increased IL-6 production, whereas IFN-γ/LIGHT-dependent Th1 chemokine induction was decreased compared with that in normal DFs. Importantly, LIGHT small interfering RNA significantly attenuated bleomycin-induced skin fibrosis, and serum LIGHT levels were elevated in patients with diffuse cutaneous SSc and positively correlated with clinical parameters reflecting skin and pulmonary fibrosis. Taken together, these results suggest that altered response of DFs to LIGHT, namely increased IL-6 production and decreased Th1 chemokine expression, contributes to the development of skin fibrosis in SSc.

• Authors: Tetsuya Ikawa, Yohei Ichimura, Takuya Miyagawa, Yuki Fukui, Satoshi Toyama, Jun Omatsu, Kentaro Awaji, Yuta Norimatsu, Yusuke Watanabe, Ayumi Yoshizaki, Shinichi Sato, Yoshihide Asano
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 142 Issue 6 Pg. 1541-1551.e3 (06 2022) ISSN: 1523-1747 [Electronic] United States
• PMID: 34838790 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Chemokines
• Cytokines
• IL6 protein, human
• Interleukin-6
• Proto-Oncogene Protein c-fli-1
• RNA, Small Interfering
• TNFSF14 protein, human
• Tnfsf14 protein, mouse
• Tumor Necrosis Factor Ligand Superfamily Member 14
• interleukin-6, mouse
• Bleomycin

Topics

• Animals
• Bleomycin (toxicity)
• Chemokines (metabolism)
• Cytokines (metabolism)
• Disease Models, Animal
• Fibroblasts (metabolism)
• Fibrosis
• Humans
• Interleukin-6 (metabolism)
• Mice
• Proto-Oncogene Protein c-fli-1
• RNA, Small Interfering (metabolism)
• Scleroderma, Systemic (metabolism)
• Skin (pathology)
• Tumor Necrosis Factor Ligand Superfamily Member 14 (genetics, metabolism)