RT Journal Article
SR Electronic
T1 The Downregulation of microRNA let-7a Contributes to the Excessive Expression of Type I Collagen in Systemic and Localized Scleroderma
JF The Journal of Immunology
JO J. Immunol.
FD American Association of Immunologists
SP 1200822
DO 10.4049/jimmunol.1200822
A1 Makino, Katsunari
A1 Jinnin, Masatoshi
A1 Hirano, Ayaka
A1 Yamane, Keitaro
A1 Eto, Mitsuhiko
A1 Kusano, Takamitsu
A1 Honda, Noritoshi
A1 Kajihara, Ikko
A1 Makino, Takamitsu
A1 Sakai, Keisuke
A1 Masuguchi, Shinichi
A1 Fukushima, Satoshi
A1 Ihn, Hironobu
YR 2013
UL http://www.jimmunol.org/content/early/2013/03/15/jimmunol.1200822.abstract
AB Systemic and localized scleroderma (SSc and LSc) is characterized by excessive deposition of collagen and tissue fibrosis in the skin. Although they have fundamental common characteristics including autoimmunity, little is known about the exact mechanism that mediates the excessive collagen expression in these disorders. In the current study, we tried to evaluate the possibility that microRNAs (miRNAs) play some roles in the pathogenesis of fibrosis seen in these diseases. miRNA expression patterns were evaluated by miRNA array analysis, real-time PCR, and in situ hybridization. The function of miRNAs in dermal fibroblasts was assessed using miRNA inhibitors, precursors, or protectors. In the mouse model of bleomycin-induced dermal sclerosis, the overexpression of miRNAs was performed by i.p. miRNA injection. We demonstrated let-7a expression was downregulated in SSc and LSc skin both in vivo and in vitro, compared with normal or keloid skin. The inhibition or overexpression of let-7a in human or mouse skin fibroblasts affected the protein expression of type I collagen or luciferase activity of collagen 3′-untranslated region. Also, we found let-7a was detectable and quantitative in the serum and investigated serum let-7a levels in patients with SSc or LSc. let-7a concentration was significantly decreased in these patients, especially in LSc patients. Moreover, we revealed that the intermittent overexpression of let-7a in the skin by i.p. miRNA injection improved the skin fibrosis induced by bleomycin in mice. Investigation of more detailed mechanisms of miRNA-mediated regulation of collagen expression may lead to new therapeutic approaches against SSc and LSc.