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

• Published in: Arthritis research & therapy 2015-07, Vol.17
• Main Authors: Baraut, Julie, Farge, Dominique, Jean-Louis, Francette, Masse, Ingrid, Grigore, Elena Ivan, Arruda, Lucas C. M, Lama, Verrecchia, Franck, Michel, Laurence
• Format: Article
• Language: English
• Subjects: Analysis; Bone morphogenetic proteins; Chromatin; Collagen; DNA binding proteins; Genetic research; Health aspects; Interleukins; Protein biosynthesis; RNA; Scleroderma (Disease); Statistics; Systemic scleroderma; T cells; Transforming growth factors
• ISSN: 1478-6354
• DOI: 10.1186/s13075-015-0708-0

Introduction Transforming growth factor (TGF)-[beta] 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-[beta] alters IL-13 production in T lymphocytes from patients with SSc from that seen in those of healthy donors. Methods IL-13 mRNA and protein synthesis under TFG-[beta] 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. Results TGF-[beta] induced a significant decrease in IL-13 mRNA and protein levels in lymphocytes from healthy donors (mean [[+ or -]SD] inhibition of 30 % [+ or -] 10 % and 20 % [+ or -] 7 %, respectively; p < 0.05). In contrast, TGF-[beta] promoted a significant increase in IL-13 mRNA levels and IL-13 synthesis by CD4.sup.+ and CD8.sup.+ T-cell subtypes from patients with SSc, with respective increases of 2.4 [+ or -] 0.3-fold, 1.6 [+ or -] 0.05-fold and 2.7 [+ or -] 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-[beta] on IL-13 production. Conclusions These results demonstrate that TGF-[beta] 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.