期刊
ARTHRITIS AND RHEUMATISM
卷 65, 期 5, 页码 1347-1356出版社
WILEY
DOI: 10.1002/art.37860
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资金
- Swiss National Science Foundation [31003A_124941/1, 310030_140791]
- Association des Sclerodermiques de France
- Societe Francaise de Rhumatologie, France
- Manodori Foundation, Reggio Emilia, Italy
- IRCCS Istituto Auxologico Italiano, Italy
- Swiss National Science Foundation (SNF) [310030_140791, 31003A_124941] Funding Source: Swiss National Science Foundation (SNF)
Objective Levels of interleukin-17A (IL-17A) have been found to be increased in synovial fluid from individuals with systemic sclerosis (SSc). This study was undertaken to investigate whether IL-17Aproducing cells are present in affected SSc skin, and whether IL-17A exerts a role in the transdifferentiation of myofibroblasts. Methods Skin biopsy samples were obtained from the involved skin of 8 SSc patients and from 8 healthy control donors undergoing plastic surgery. Immunohistochemistry and multicolor immunofluorescence techniques were used to identify and quantify the cell subsets in vivo, including IL-17A+, IL-4+, CD3+, tryptase-positive, -smooth muscle actin (-SMA)positive, myeloperoxidase-positive, and CD1a+ cells. Dermal fibroblast cell lines were generated from all skin biopsy samples, and quantitative polymerase chain reaction, Western blotting, and solid-phase assays were used to quantify -SMA, type I collagen, and matrix metalloproteinase 1 (MMP-1) production by the cultured fibroblasts. Results IL-17A+ cells were significantly more numerous in SSc skin than in healthy control skin (P = 0.0019) and were observed to be present in both the superficial and deep dermis. Involvement of both T cells and tryptase-positive mast cells in the production of IL-17A was observed. Fibroblasts positive for -SMA were found adjacent to IL-17A+ cells, but not IL-4+ cells. However, IL-17A did not induce -SMA expression in cultured fibroblasts. In the presence of IL-17A, the -SMA expression induced in response to transforming growth factor was decreased, while MMP-1 production was directly enhanced. Furthermore, the frequency of IL-17A+ cells was higher in the skin of SSc patients with greater severity of skin fibrosis (lower global skin thickness score). Conclusion IL-17A+ cells belonging to the innate and adaptive immune system are numerous in SSc skin. IL-17A participates in inflammation while exerting an inhibitory activity on myofibroblast transdifferentiation. These findings are consistent with the notion that IL-17A has a direct negative-regulatory role in the development of dermal fibrosis in humans.
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