Nakayama Wakana, Jinnin Masatoshi, Tomizawa Yukiko, Nakamura Kayo, Kudo Hideo, Inoue Kuniko, Makino Katsunari, Honda Noritoshi, Kajihara Ikko, Fukushima Satoshi, Ihn Hironobu
Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku Kumamoto, Japan.
Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku Kumamoto, Japan
Rheumatology (Oxford). 2017 Jan;56(1):145-155. doi: 10.1093/rheumatology/kew336. Epub 2016 Oct 15.
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.
白细胞介素-12（IL-12）家族细胞因子的过表达与系统性硬化症（SSc）的发病机制有关，但其确切作用仍不清楚。本研究旨在探讨IL-23对细胞外基质表达的调控及其对SSc表型的影响。
采用PCR芯片和实时定量PCR检测mRNA表达。通过免疫印迹和免疫组织化学染色检测蛋白质表达水平。在博来霉素诱导的SSc小鼠模型中，检测IL-23对体内皮肤纤维化的影响。
在IL-12家族成员中，IL-23可降低培养的正常皮肤成纤维细胞中I型胶原蛋白的表达。我们发现miR-4458和miR-18a介导了IL-23对胶原蛋白表达的下调。相反，IL-23可上调SSc成纤维细胞中I型胶原蛋白的表达。IL-23对SSc成纤维细胞的这种矛盾作用也由miR-4458和miR-18a表达之间的平衡介导。此外，我们发现向小鼠皮肤注射IL-23可加速皮肤纤维化。
本研究首次报道两种微小RNA（miRNA）的平衡参与了SSc成纤维细胞中胶原蛋白的失调。阐明IL-23在SSc皮肤中对组织纤维化的调控机制可能有助于更好地理解这种疾病并开发新的治疗方法。
