title: Dysregulated interleukin-23 signalling contributes to the increased collagen production in scleroderma fibroblasts via balancing microRNA expression.
abstract: The overexpression of IL-12 family cytokines is implicated in the pathogenesis of SSc, but their exact role is still unclear. The aim of this study was to investigate the regulation of extracellular matrix expression by IL-23 and its contribution to the phenotype of SSc.
  
  
  
  The mRNA expression was determined by PCR array and real-time PCR. The expression levels of proteins were determined by immunoblotting and immunohistochemical staining. The effect of IL-23 on dermal fibrosis in vivo was examined in a mouse model of SSc induced by bleomycin injection.
  
  
  
  Among the IL-12 family members, IL-23 decreased expression of type I collagen protein in cultured normal dermal fibroblasts. We found that miR-4458 and miR-18a mediated the reduction of collagen expression by IL-23. On the contrary, IL-23 up-regulated type I collagen expression in SSc fibroblasts. The paradoxical effects of IL-23 in SSc fibroblasts were also mediated by the balance between miR-4458 and miR-18a expression. Moreover, we revealed that injection of IL-23 into the mouse skin accelerated skin fibrosis.
  
  
  
  This is the first study to report that the balance of two miRNAs is involved in the collagen dysregulation in SSc fibroblasts. Clarification of the regulatory mechanism of tissue fibrosis by IL-23 in SSc skin may lead to a better understanding of this disease and new therapeutic approaches.
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku Kumamoto, Japan.
authors.forename: Wakana
authors.initials: W
authors.lastname: Nakayama
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku Kumamoto, Japan mjin@kumamoto-u.ac.jp.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Jinnin
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku Kumamoto, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Tomizawa
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku Kumamoto, Japan.
authors.forename: Kayo
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku Kumamoto, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Kudo
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku Kumamoto, Japan.
authors.forename: Kuniko
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku Kumamoto, Japan.
authors.forename: Katsunari
authors.initials: K
authors.lastname: Makino
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku Kumamoto, Japan.
authors.forename: Noritoshi
authors.initials: N
authors.lastname: Honda
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku Kumamoto, Japan.
authors.forename: Ikko
authors.initials: I
authors.lastname: Kajihara
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku Kumamoto, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fukushima
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku Kumamoto, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Ihn
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D001761:Bleomycin / Q000633:toxicity; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D024042:Collagen Type I / Q000187:drug effects* / Q000378:metabolism; D055513:Connective Tissue Growth Factor; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D018664:Interleukin-12 / Q000494:pharmacology*; D053759:Interleukin-23 / Q000276:immunology / Q000494:pharmacology*; D064094:Interleukin-27 / Q000494:pharmacology*; D051379:Mice; D035683:MicroRNAs / Q000187:drug effects* / Q000235:genetics; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D045743:Scleroderma, Diffuse / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D000903:Antibiotics, Antineoplastic; D024042:Collagen Type I; D053759:Interleukin-23; D064094:Interleukin-27; D035683:MicroRNAs; D001761:Bleomycin; D055513:Connective Tissue Growth Factor; D018664:Interleukin-12; D003094:Collagen
keywords: collagen; cytokine; fibrosis; microRNA; scleroderma