Abstract
BackgroundThe 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.ObjectiveTo 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.MethodsExpression 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.ResultsHS 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.ConclusionIL-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.
Highlights
Scarring is an expected result of wound healing [1,2]
hypertrophic scar (HS) tissue and primary HS fibroblasts (HSFs) were characterized by expression of the Interleukin 10 (IL-10) receptor and by high expression of fibrotic markers relative to normal controls
The results showed that IL-10 down-regulated collagen expression, upregulated matrix metalloproteinase (MMP) 1 and MMP8 expression, and repressed the transformation of fibroblasts into alphasmooth muscle actin (a-SMA)-positive myofibroblasts, leading to the degradation of abnormally deposited extracellular matrix (ECM) components and a decrease in excessive ECM secretion
Summary
In some individuals the wound healing process leads to development of a fibrotic hypertrophic scar (HS) characterized by raised, red and inflexible skin tissue. Such scars can cause serious functional and cosmetic problems and result in psychological and physical suffering [3,4,5,6]. Interleukin 10 (IL-10) was first described as a cytokine-synthesis inhibitory factor with anti-inflammatory functions [9,10]. As a major immunosuppressive and anti-inflammatory factor, IL-10 plays a pivotal role in wound healing [11,13]. Relatively little is known about the mechanisms underlying IL-10-mediated anti-fibrotic and scar-improvement actions
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