Transforming growth factor-β increases interleukin-13 synthesis via GATA-3 transcription factor in T-lymphocytes from patients with systemic sclerosis

Abstract

IntroductionTransforming growth factor (TGF)-β and interleukin (IL)-13 play a crucial role in the pathogenesis of systemic sclerosis (SSc), partly through activation of collagen production that leads to fibrosis. The aim of the present study was to determine whether TFG-β alters IL-13 production in T lymphocytes from patients with SSc from that seen in those of healthy donors.MethodsIL-13 mRNA and protein synthesis under TFG-β exposure was measured in circulating T lymphocytes from healthy donors and patients with SSc and also in the Jurkat Th2 T-cell line, using quantitative real-time PCR and fluorescence-activated cell sorting analysis, respectively. The involvement of Smad and GATA-3 transcription factors was assessed by using specific inhibitors and small interfering RNA, and the binding capacity of GATA-3 to the IL-13 gene promoter was evaluated by chromatin immunoprecipitation assay.ResultsTGF-β induced a significant decrease in IL-13 mRNA and protein levels in lymphocytes from healthy donors (mean [±SD] inhibition of 30 % ± 10 % and 20 % ± 7 %, respectively; p < 0.05). In contrast, TGF-β promoted a significant increase in IL-13 mRNA levels and IL-13 synthesis by CD4+ and CD8+ T-cell subtypes from patients with SSc, with respective increases of 2.4 ± 0.3-fold, 1.6 ± 0.05-fold and 2.7 ± 0.02-fold. The involvement of the Smad signaling pathway and upregulation of GATA-3 binding capacity on the IL-13 promoter in lymphocytes from patients with SSc contributed to the effect of TGF-β on IL-13 production.ConclusionsThese results demonstrate that TGF-β upregulates IL-13 synthesis through GATA-3 expression in the T lymphocytes of patients with SSc, confirming that the GATA-3 transcription factor can be regarded as a novel therapeutic target in patients with SSc.

CCL3, IL‐7, IL‐13 and IFNγ transcripts are increased in skin's biopsy of systemic sclerosis

“…CCL3 participates in the recruitment of monocytes and helper T lymphocytes and upregulation of the expression of adhesion molecules, thus allowing diapedesis, helping to recruit fibrosis myofibroblasts, macrophages and peripheral blood mononuclear cells towards sites of tissue injury, with resultant collagen production induction, thus contributing to fibrosis in SSc . IL‐13 is a potent modulator of monocytes and B‐cell function and, among its many functions, is known to be involved in tissue remodelling and fibrosis, especially in SSc . In addition, IL‐13 has the ability to suppress the production of pro‐inflammatory cytokines by monocytes/macrophages, such as TNF, IL‐1, IL‐8 and CCL3 .…”

Sphingosine-1-Phosphate Receptor 5 Modulates Early-Stage Processes during Fibrogenesis in a Mouse Model of Systemic Sclerosis: A Pilot Study

“…The pathophysiological relevance of GATA-3 has been proven by several studies. Referred to those, the upregulation of GATA-3 in T cells increases IL-13 synthesis ( 68 , 69 ). Especially IL-13, produced by CD8+CD28− scleroderma T cells, enhances COL1A1 protein expression in dermal fibroblasts ( 70 ).…”

Transforming growth factor-β signaling in systemic sclerosis

“…TGF-β is a key fibrogenic cytokine that regulates a multitude of biological functions including cell proliferation, differentiation, apoptosis, tissue homeostasis and regeneration [ 45 , 63 – 64 ] . Due to its diversified activities, malfunctions in TGF-β-related processes can lead to severe, multifaceted diseases.…”

“…The TGF-β type II receptor is a serine/threonine receptor kinase that upon activation causes the phosphorylation of a type I receptor [ 65 ] . Phosphorylation of TβRI initiates the phosphorylation of the Smad2 or 3 protein, which then forms a Smad complex with a Smad4 protein [ 45 , 63 – 65 ] . This activated Smad complex then enters the nucleus of a cell where it acts as a transcription factor [ 12 ] .…”