EBI3 Downregulation Contributes to Type I Collagen Overexpression in Scleroderma Skin.
IL-12 family cytokines are implicated in the pathogenesis of various autoimmune diseases, but their role in the regulation of extracellular matrix expression and its contribution to the phenotype of systemic sclerosis (SSc) remain to be elucidated. Among the IL-12 family members, IL-35 decreases type I collagen expression in cultured dermal fibroblasts. IL-35 consists of p35 and EBI3 subunits, and EBI3 alone could downregulate the protein and mRNA expression of type I or type III collagen in the presence or absence of TGF-β costimulation. We found that collagen mRNA stability was reduced by EBI3 via the induction of miR-4500. The IL-35 levels in the sera or on the surface of T cells were not altered in SSc patients, while EBI3 expression was decreased in the keratinocytes of the epidermis and regulatory T cells of the dermis in SSc skin compared with normal skin, which may induce collagen synthesis in SSc dermal fibroblasts. We also found that gp130, the EBI3 receptor, was expressed in both normal and SSc fibroblasts. Moreover, we revealed that EBI3 supplementation by injection into the skin improves mice skin fibrosis. Decreased EBI3 in SSc skin may contribute to an increase in collagen accumulation and skin fibrosis. Clarifying the mechanism regulating the extracellular matrix expression by EBI3 in SSc skin may lead to better understanding of this disease and new therapeutic strategies using ointment or microinjection of the subunit.
Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Hideo
http://orcid.org/0000-0001-8920-1447
H
Kudo
Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Zhongzhi
Z
Wang
Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan mjin@kumamoto-u.ac.jp.
Masatoshi
M
Jinnin
Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Wakana
W
Nakayama
Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Kuniko
K
Inoue
Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Noritoshi
N
Honda
Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Taiji
T
Nakashima
Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Ikko
I
Kajihara
Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Katsunari
K
Makino
Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Takamitsu
T
Makino
Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Satoshi
S
Fukushima
Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Hironobu
H
Ihn
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D024042:Collagen Type I / Q000235:genetics / Q000276:immunology*; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology*; D005260:Female; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D020871:RNA Stability / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology; D018121:Receptors, Cytokine / Q000235:genetics / Q000276:immunology*; D045743:Scleroderma, Diffuse / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D012867:Skin / Q000276:immunology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology
D024042:Collagen Type I; C097732:EBI3 protein, human; C499601:Ebi3 protein, mouse; C494200:Il6st protein, mouse; D007378:Interleukins; D015778:Minor Histocompatibility Antigens; D012333:RNA, Messenger; D018121:Receptors, Cytokine; D050822:Cytokine Receptor gp130