Co-ordinate increase in the expression of type I and type III collagen genes in progressive systemic sclerosis fibroblasts

Jimenez, Sergio A.; Feldman, George M.; Bashey, Reza I.; Bienkowski, Robert S.; Rosenbloom, J.

doi:10.1042/bj2370837

Cited by 168 publications

(73 citation statements)

References 31 publications

(22 reference statements)

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“…The principal effect of TGF-b1 on mesenchymal cells is the stimulation of ECM deposition. Dermal fibroblasts from affected SSc skin cultured in vitro display an increased transcription of various collagens, mainly type I collagen, which consists of a1(I) and a2(I) collagen (7)(8)(9)(10), whereas the blockade of TGF-b1 signaling with anti-TGFb1-neutralizing Abs abolishes the increased expression of collagen mRNA in cultured SSc fibroblasts (11). However, the TGF-b1 levels in the culture media of SSc fibroblasts do not increase in comparison with those of normal fibroblasts (11), thus suggesting that the activation of fibroblasts in SSc may be a result of the intrinsic TGF-b1 activation.…”

mentioning

confidence: 99%

Impaired IL-17 Signaling Pathway Contributes to the Increased Collagen Expression in Scleroderma Fibroblasts

Nakashima

Jinnin

Yamane

et al. 2012

The Journal of Immunology

185

137

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Among IL-17 families, IL-17A and IL-17F share amino acid sequence similarity and bind to IL-17R type A. IL-17 signaling is implicated in the pathogenesis of various autoimmune diseases, but its role in the regulatory mechanism of extracellular matrix expression and its contribution to the phenotype of systemic sclerosis (SSc) both remain to be elucidated. This study revealed that IL-17A expression was significantly increased in the involved skin and sera of SSc patients, whereas the IL-17F levels did not increase. In contrast, the expression of IL-17R type A in SSc fibroblasts significantly decreased in comparison with that in normal fibroblasts, due to the intrinsic TGF-β1 activation in these cell types. Moreover, IL-17A, not IL-17F, reduced the protein expression of α1(I) collagen and connective tissue growth factor. miR-129-5p, one of the downregulated microRNAs in SSc fibroblasts, increased due to IL-17A and mediated the α1(I) collagen reduction. These results suggest that IL-17A signaling, not IL-17F, has an antifibrogenic effect via the upregulation of miR-129-5p and the downregulation of connective tissue growth factor and α1(I) collagen. IL-17A signaling is suppressed due to the downregulation of the receptor by the intrinsic activation of TGF-β1 in SSc fibroblasts, which may amplify the increased collagen accumulation and fibrosis characteristic of SSc. Increased IL-17A levels in the sera and involved skin of SSc may be due to negative feedback. Clarifying the novel regulatory mechanisms of fibrosis by the cytokine network consisting of TGF-β and IL-17A may lead to a new therapeutic approach for this disease.

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mentioning

confidence: 99%

Impaired IL-17 Signaling Pathway Contributes to the Increased Collagen Expression in Scleroderma Fibroblasts

Nakashima

Jinnin

Yamane

et al. 2012

The Journal of Immunology

185

137

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“…The overproduction of collagen by scleroderma fibroblasts is associated with an increase in collagen messenger RNA levels (5). Fibroblast-specific autoantibodies have been detected in the serum of scleroderma patients, and in vitro data suggest that these antibodies can induce fibroblast activation, as measured by increases in expression of proinflammatory cytokines (6).…”

mentioning

confidence: 99%

Lack of detection of agonist activity by antibodies to platelet‐derived growth factor receptor α in a subset of normal and systemic sclerosis patient sera

Loizos¹,

LaRiccia²,

Weiner³

et al. 2009

Arthritis & Rheumatism

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Objective. To investigate whether agonist antiplatelet-derived growth factor receptor ␣ (anti-PDGFR␣) antibodies are present in the serum of patients with systemic sclerosis (SSc; scleroderma).Methods. Sera were obtained from healthy subjects and scleroderma patients. An electrochemiluminescence binding assay was performed for detection of serum autoantibodies to PDGFR␣, PDGFR␤, epidermal growth factor receptor (EGFR), and colonystimulating factor receptor 1 (CSFR1). Serum immunoglobulin was purified by protein A/G chromatography. To assess Ig agonist activity, PDGFR␣-expressing cells were incubated with pure Ig and the level of receptor phosphorylation determined in an enzyme-linked immunoassay, as well as by Western blotting. Ig agonist activity was also assessed in a mitogenic assay and by MAP kinase activation in a PDGFR␣-expressing cell line.Results. Sera from 34.3% of the healthy subjects and 32.7% of the SSc patients contained detectable autoantibodies to PDGFR␣ and PDGFR␤, but not EGFR or CSFR1. Purified Ig from these sera was shown to retain PDGFR binding activity and, at 200-1,000 g/ml, exhibited no agonist activity in a cell-based PDGFR␣ phosphorylation assay and did not stimulate a mitogenic response or MAP kinase activation in a PDGFR␣-expressing cell line. Two purified Ig samples that were unable to bind PDGFR␣ did exhibit binding activity to a nonglycosylated form of PDGFR␣.Conclusion. Although approximately one-third of sera from scleroderma patients contained detectable autoantibodies to PDGFR, these antibodies were not specific to scleroderma, since they were also detected in a similar percentage of samples from normal subjects. PDGFR␣ agonist activity was not demonstrated when purified Ig from these sera was tested in cell-based assays.

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“…Fibroblasts from affected systemic sclerosis skin cultured in vitro produce excessive amounts of various collagens (6,7) and display increased transcription of the corresponding genes (7)(8)(9)(10). However, the mechanisms responsible for the increased transcriptional activity of collagen genes in systemic sclerosis fibroblasts are not fully understood.…”

Section: Discussionmentioning

confidence: 99%

“…Dermal fibroblast cell lines were established from patients with systemic sclerosis who fulfilled the American College of Rheumatology (formerly, the American Rheumatism Association) criteria for the classification of the disease (22). To avoid variability introduced by heterogeneity of the clinical characteristics and differences in the stage of evolution of systemic sclerosis, only cells from untreated patients with diffuse systemic sclerosis of recent onset and rapid progression were studied, as described previously (7,16). The cell lines were obtained from full-thickness skin biopsy tissue surgically excised for diagnostic purposes from the leading edge of clinically apparent systemic sclerosis lesions.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of systemic sclerosis dermal fibroblast type I collagen production and gene expression by simvastatin

Louneva¹,

Huaman²,

Fertala³

et al. 2006

Arthritis & Rheumatism

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Objective. To examine whether statins are capable of modulating collagen gene expression in cultured systemic sclerosis dermal fibroblasts.Methods. Cultured dermal fibroblasts from 3 patients with diffuse systemic sclerosis of recent onset were treated with 5 M and 10 M of simvastatin for 3 or 4 days. Morphologic features, cytotoxicity, and type I collagen production and messenger RNA (mRNA) levels in the fibroblasts were examined. The effects of mevalonate, geranylgeranyl pyrophosphate (GGPP), and farnesyl pyrophosphate (FPP), which are lipids downstream from the hydroxymethylglutaryl-coenzyme A block, were also examined. Transient transfections with COL1A1 promoter-reporter constructs and electrophoretic gel mobility shift assays were utilized to examine COL1A1 transcription and Sp1 and CCAAT-box binding factor (CBF) binding.Results. Simvastatin did not cause morphologic changes or cytotoxicity in the fibroblasts, even after 4 days of treatment. Type I collagen production and mRNA levels showed a potent and dose-related inhibition following 3 and 4 days of treatment. The inhibition of collagen gene expression by simvastatin was completely reversed by mevalonate and GGPP, but not by FPP. The statin effects occurred at the transcriptional level and involved the proximal COL1A1 promoter region encompassing ؊174 bp. A significant reduction in Sp1 and CBF binding activity was also found in simvastatin-treated cells.

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Co-ordinate increase in the expression of type I and type III collagen genes in progressive systemic sclerosis fibroblasts

Cited by 168 publications

References 31 publications

Impaired IL-17 Signaling Pathway Contributes to the Increased Collagen Expression in Scleroderma Fibroblasts

Impaired IL-17 Signaling Pathway Contributes to the Increased Collagen Expression in Scleroderma Fibroblasts

Lack of detection of agonist activity by antibodies to platelet‐derived growth factor receptor α in a subset of normal and systemic sclerosis patient sera

Inhibition of systemic sclerosis dermal fibroblast type I collagen production and gene expression by simvastatin

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