title: Anti-fibrotic actions of interleukin-10 against hypertrophic scarring by activation of PI3K/AKT and STAT3 signaling pathways in scar-forming fibroblasts.
abstract: BACKGROUND
  The hypertrophic scar (HS) is a serious fibrotic skin condition and a major clinical problem. Interleukin-10 (IL-10) has been identified as a prospective scar-improving compound based on preclinical trials. Our previous work showed that IL-10 has anti-fibrotic effects in transforming growth factor (TGF)-β1-stimulated fibroblasts, as well as potential therapeutic benefits for the prevention and reduction of scar formation. However, relatively little is known about the mechanisms underlying IL-10-mediated anti-fibrotic and scar-improvement actions.
  
  
  OBJECTIVE
  To explore the expression of the IL-10 receptor in human HS tissue and primary HS fibroblasts (HSFs), and the molecular mechanisms contributing to the anti-fibrotic and scar-improvement capabilities of IL-10.
  
  
  METHODS
  Expression of the IL-10 receptor was assessed in HS tissue and HSFs by immunohistochemistry, immunofluorescence microscopy, and polymerase chain reaction analysis. Primary HSFs were treated with IL-10, a specific phosphatidylinositol 3 kinase (PI3K) inhibitor (LY294002) or a function-blocking antibody against the IL-10 receptor (IL-10RB). Next, Western blot analysis was used to evaluate changes in the phosphorylation status of AKT and signal transducers and activators of transcription (STAT) 3, as well as the expression levels of fibrosis-related proteins.
  
  
  RESULTS
  HS tissue and primary HSFs were characterized by expression of the IL-10 receptor and by high expression of fibrotic markers relative to normal controls. Primary HSFs expressed the IL-10 receptor, while IL-10 induced AKT and STAT3 phosphorylation in these cells. In addition, LY294002 blocked AKT and STAT phosphorylation, and also up-regulated expression levels of type I and type III collagen (Col 1 and Col 3) and alpha-smooth muscle actin (α-SMA) in IL-10-treated cells. Similarly, IL-10RB reduced STAT3/AKT phosphorylation and blocked the IL-10-mediated mitigation of fibrosis in HSFs.
  
  
  CONCLUSIONS
  IL-10 apparently inhibits fibrosis by activating AKT and STAT3 phosphorylation downstream of the IL-10 receptor, and by facilitating crosstalk between the PI3K/AKT and STAT3 signal transduction pathways.
authors.affiliation: Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Jihong
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Guan
authors.affiliation: Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Weixia
authors.initials: W
authors.lastname: Cai
authors.affiliation: Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Xiaozhi
authors.initials: X
authors.lastname: Bai
authors.affiliation: Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Fang
authors.affiliation: Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Yaojun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Hongtao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Su
authors.affiliation: Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Dahai
authors.initials: D
authors.lastname: Hu
authors.affiliation: Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Xiongxiang
authors.initials: X
authors.lastname: Zhu
mesh_terms: D017439:Cicatrix, Hypertrophic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects* / Q000473:pathology; D005355:Fibrosis; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology* / Q000627:therapeutic use; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D053701:Receptors, Interleukin-10 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D012867:Skin / Q000473:pathology
chemical_list: D053701:Receptors, Interleukin-10; D050796:STAT3 Transcription Factor; D016753:Interleukin-10; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt