Expression of interleukin-4 in scleroderma skin specimens and scleroderma fibroblast cultures. Potential role in fibrosis

Salmon-Ehr, V.

doi:10.1001/archderm.132.7.802

Cited by 46 publications

(55 citation statements)

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“…This functional heterogeneity in lesional skin, which has previously been observed by others (19,39,42), may be inherent to SSc or to particular phases of the disease.…”

Section: Discussionsupporting

confidence: 60%

“…Collagen synthesis is up-regulated in fibroblasts in the proximity of infiltrating T cells (15)(16)(17), which suggests that T cells may directly or indirectly dysregulate the metabolism of fibroblasts and participate in the development of fibrosis. According to this perspective, Th2 cells may act by releasing profibrotic cytokines (IL-4, IL-13) (18)(19)(20) that induce fibroblasts to produce extracellular matrix components, and Th1 cells by releasing antifibrotic cytokines (interferon-␥ [IFN␥]) that inhibit extracellular matrix production (21). In addition, T lymphocytes may act directly on fibroblasts by cell-cell contact (21)(22)(23), and their effect may be mediated by other cells such as macrophages (24).…”

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confidence: 99%

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Presence of CD4+CD8+ double‐positive T cells with very high interleukin‐4 production potential in lesional skin of patients with systemic sclerosis

Parel¹,

Aurrand-Lions²,

Scheja³

et al. 2007

Arthritis & Rheumatism

129

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Objective. Fibrotic skin changes in systemic sclerosis (SSc) are preceded by the appearance of an inflammatory infiltrate rich in T cells. Since no direct comparison with T cells in normal skin has been performed previously, this study was undertaken to functionally characterize T cells in the skin of patients with early active SSc and in normal skin.Methods. We characterized coreceptor expression, T cell receptor (TCR) usage, cytokine production, and helper and cytolytic activity of T cell lines and clones established from skin biopsy specimens from 6 SSc patients and 4 healthy individuals. Immunofluorescence analysis of skin biopsy and peripheral blood samples was performed to confirm the presence of specific subsets in vivo.Results. A distinct subset expressing both CD4 and CD8␣/␤ coreceptors at high levels (double-positive [DP]) was present in T cell lines from SSc and normal skin. DP T cells actively transcribed both accessory molecules, exerted clonally distributed cytolytic and helper activity, and expressed TCR clonotypes distinct from those in CD4؉ or CD8؉ single-positive (SP) T cells. In SSc skin, DP T cells produced very high levels of interleukin-4 (IL-4) compared with CD4؉ SP T cells. Furthermore, DP T cells were directly identified in SSc skin, thus providing evidence that they are a distinct subset in vivo.Conclusion. The present findings show that T cells with the unusual CD4؉CD8؉ DP phenotype are present in the skin. Their very high level of IL-4 production in early active SSc may contribute to enhanced extracellular matrix deposition by fibroblasts.

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“…This functional heterogeneity in lesional skin, which has previously been observed by others (19,39,42), may be inherent to SSc or to particular phases of the disease.…”

Section: Discussionsupporting

confidence: 60%

mentioning

confidence: 99%

Presence of CD4+CD8+ double‐positive T cells with very high interleukin‐4 production potential in lesional skin of patients with systemic sclerosis

Parel¹,

Aurrand-Lions²,

Scheja³

et al. 2007

Arthritis & Rheumatism

129

View full text Add to dashboard Cite

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“…29 In humans, the progression of idiopathic pulmonary fibrosis is associated with IL-4 production. 30 High levels of IL-4 expression have also been found in the fibrotic skin tissues of patients with scleroderma, 31 and IL-4 is important in collagen production by human conjunctival fibroblasts. 29 IL-4 may impact the course of fibrotic liver damage.…”

mentioning

confidence: 99%

Interleukin-4 induces the activation and collagen production of cultured human intrahepatic fibroblasts via the STAT-6 pathway

Aoudjehane

Pissaia

Scatton

et al. 2008

Laboratory Investigation

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Interleukin-4 (IL-4) is overexpressed in liver grafts in a context of severe recurrent hepatitis C, during which the development of fibrosis is dramatically accelerated. In this study, we examined the effects of IL-4 on the activation and collagen production of cultured human intrahepatic (myo)fibroblasts (hIHFs), and investigated the underlying mechanisms. The myofibroblastic nature of cells was evaluated morphologically using activation markers (smooth muscle a-actin, vimentin and prolyl 4-hydroxylase). Quiescent hIHFs were obtained by cell incubation in serum-free medium or cell culture on Matrigel. We first analyzed IL-4 receptor expression, STAT-6 activation by IL-4, and STAT-6 inhibition by an anti-IL-4 antibody or by STAT-6 small-interfering RNA (siRNA) transfection. We then focused on collagen production, using quantitative real-time PCR to analyze the effect of IL-4 on the mRNA expression of collagens I, III and IV, and on collagen levels in supernatants of hIHFs, using the Sircol collagen assay. hIHFs cultured in plastic wells appeared to be morphologically activated. The expression of activation markers was reduced by serum deprivation or culture on Matrigel, and restored by IL-4 incubation. The IL-4 receptor was expressed by hIHFs, and STAT-6 was activated following incubation with IL-4. Both anti-IL-4 antibody and STAT-6 siRNA transfection inhibited this activation. The treatment of hIHFs with IL-4 increased the mRNA expression of collagens I, III and IV (Po0.05) and elevated collagen levels in supernatants (P ¼ 0.01 vs untreated cells). Therefore, IL-4 exerts profibrotic effects by activating hIHFs and inducing collagen production and secretion. This effect requires IL4-R binding and STAT-6 activation. IL-4 may thus be involved in accelerated course of fibrogenesis during recurrent hepatitis C.

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“…Plasma levels of IL-4 and IL-13 are elevated in SSc patients compared with healthy control subjects (19,20). Th2 cytokine expression and secretion are increased in T cells isolated from newly affected SSc skin (21,22). Activated CD8ϩ T cells in bronchoalveolar lavage fluid from SSc patients with alveolitis have higher type 2 cytokine (IL-4 and IL-5) messenger RNA (mRNA) expression (12,13).…”

mentioning

confidence: 99%

T cell polarization identifies distinct clinical phenotypes in scleroderma lung disease

Boin¹,

Fanis²,

Bartlett³

et al. 2008

Arthritis & Rheumatism

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Objective. Lung involvement is the leading cause of morbidity and mortality in systemic sclerosis (SSc; scleroderma), and interstitial lung disease (ILD) is the most common pulmonary manifestation. An abnormal profibrotic Th2/Tc2-polarized T cell response is postulated to mediate tissue damage and fibrosis. The aim of this study was to investigate whether a polarized T cell phenotype in SSc is associated with lung disease or other clinical manifestations of SSc.Methods. Circulating T cells were characterized by flow cytometry in 62 patients with SSc and 36 healthy control subjects, using antibodies against CD3, CD4, CD8, chemokine receptor CCR5 (Th1/Tc1-specific), and prostaglandin D 2 receptor CRTH2 (Th2/Tc2-specific). The ratio between CCR5 and CRTH2 T cell frequencies was used to quantify type 1 (high-ratio) or type 2 (low-ratio) immune polarization.Results. Patients with SSc exhibited lower CCR5/ CRTH2 T cell ratios than those exhibited by control subjects (P < 0.0001), indicating a Th2/Tc2-polarized phenotype. Markedly reduced CCR5/CRTH2 T cell ratios were observed in SSc patients with ILD compared with SSc patients without ILD (P < 0.0001), particularly in patients with active ILD (P < 0.0001) compared with those with stable lung function. Lower CCR5/ CRTH2 ratios were strongly associated with a lower value for the percent predicted forced vital capacity (P < 0.0001). In patients with an estimated right ventricular systolic pressure >35 mm Hg, suggestive of pulmonary vascular disease, a lower value for the percent predicted diffusing capacity (DLCO) was associated with higher CCR5/CRTH2 T cell ratios (Th1/Tc1) (P ‫؍‬ 0.009), while in those with right ventricular systolic pressure <35 mm Hg, a lower value for the percent predicted DLCO correlated with lower ratios (Th2/Tc2) (P < 0.0001), as observed for ILD.

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Expression of interleukin-4 in scleroderma skin specimens and scleroderma fibroblast cultures. Potential role in fibrosis

Cited by 46 publications

References 0 publications

Presence of CD4+CD8+ double‐positive T cells with very high interleukin‐4 production potential in lesional skin of patients with systemic sclerosis

Presence of CD4+CD8+ double‐positive T cells with very high interleukin‐4 production potential in lesional skin of patients with systemic sclerosis

Interleukin-4 induces the activation and collagen production of cultured human intrahepatic fibroblasts via the STAT-6 pathway

T cell polarization identifies distinct clinical phenotypes in scleroderma lung disease

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