Botulinum toxin type A suppresses pro-fibrotic effects via the JNK signaling pathway in hypertrophic scar fibroblasts
- 121 Downloads
Hypertrophic scar is a dermal fibroproliferative disease characterized by the overproduction and deposition of extracellular matrix, and the hyperproliferation and enhanced angiogenesis of fibroblasts, along with their enhanced differentiation to myofibroblasts. Botulinum toxin type A shows potential for prevention of hypertrophic scar formation; however, its effectiveness in attenuating skin fibrosis and the related mechanism are unclear. In this study, human scar fibroblasts were cultured and stimulated with botulinum toxin type A, and the changes in fibroblast proliferation, migration, and protein expression of pro-fibrotic factors were evaluated with colorimetric, scratch, and enzyme-linked immunosorbent assays and western blotting, respectively. Botulinum toxin type A treatment decreased the proliferation and migration of human scar fibroblasts compared with those of untreated controls. Protein expression levels of pro-fibrotic factors (transforming growth factor β1, interleukin-6, and connective tissue growth factor) were also inhibited by botulinum toxin type A, whereas the JNK phosphorylation level was increased. Activation of the JNK pathway demonstrated the inhibitory effects of the toxin on human scar fibroblast proliferation and production of pro-fibrotic factors, suggesting that the suppressive effects of botulinum toxin type A are closely associated with JNK phosphorylation. Overall, this study showed that botulinum toxin type A has a suppressive effect on extracellular matrix production and scar-related factors in human scar fibroblasts in vitro, and that regulation of JNK signaling plays an important role in this process. Our results provide a theoretical basis, at the cellular level, for the therapeutic use of botulinum toxin type A.
KeywordsBotulinum toxin type A Fibroblasts JNK signaling Hypertrophic scar
This research was supported by AmorePacific Grant in 2015.
Compliance with ethical standards
Conflicts of interest
Research involving human participants and/or animals
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
- 5.Cho JS, Kang JH, Shin JM, Park IH, Lee HM (2015) Inhibitory effect of delphinidin on extracellular matrix production via the MAPK/NF-κB pathway in nasal polyp-derived fibroblasts. Allergy Asthma Immunol Res 7:276–282. https://doi.org/10.4168/aair.2015.7.3.276 CrossRefPubMedPubMedCentralGoogle Scholar
- 26.Sawamura D, Meng X, Ina S, Sato M, Tamai K, Hanada K, Hashimoto I (1998) Induction of keratinocyte proliferation and lymphocytic infiltration by in vivo introduction of the IL-6 gene into keratinocytes and possibility of keratinocyte gene therapy for inflammatory skin diseases using IL-6 mutant genes. J Immunol 161:5633–5639Google Scholar
- 28.Wilson AM (2006) Use of botulinum toxin type A to prevent widening of facial scars. Plast Reconstr Surg 117:1758–1766. https://doi.org/10.1097/01.prs.0000209944.45949.d1 (discussion 1767–1758) CrossRefGoogle Scholar