Session Type: Abstract Submissions (ACR)
IL-10 is an immune-regulatory cytokine that is expressed by a wide range of cells and tissues. It plays a central role in the regulation of the innate and adaptive immune system. IL-10 is elevated in the serum and tissues of patients with the autoimmune disorder systemic lupus erythematosus (SLE). SLE is characterized by autoantibody production, immune complex formation, and altered cytokine expression. Because IL-10 exhibits B cell-promoting effects, it has been suggested as a contributor to autoantibody production and tissue damage in SLE. In this study, we aimed to determine molecular events governing T cell-derived IL-10 expression in health and disease.
To achieve this, we forced the expression of the transcription factors Stat3 or Stat5, or inhibited them through siRNAs or chemical inhibitors in human T cells. Furthermore, IL10 reporter constructs have been utilized to determine the relative contribution of Stat3/5 on specific regulatory elements in the IL10proximal promoter and an intronic enhancer. The influence of two major epigenetic events, DNA methylation and histone acetylation, on IL-10 expression has been determined using MeDIP or ChIP assays. Furthermore, we determined potential interactions between Stat transcription factors and the transcriptional co-regulator p300, using transfection systems, siRNA and chemical inhibition strategies, and proximity ligation assays.
We link reduced DNA methylation of IL10 regulatory regions with increased recruitment of Stat transcription factors. IL-10 is regulated by both Stat3 and Stat5 through their differential recruitment to the IL10 promoter (Stat3) and an intronic enhancer (Stat5). Stat3 and Stat5 trans-activate regulatory elements and induce epigenetic remodeling of IL10through their interaction with the histone acetyltransferase p300. Of note, in T cells from SLE patients, activation of Stat3 is increased, resulting in enhanced recruitment to regulatory regions and competitive replacement of Stat5 at the intronic enhancer, subsequently promoting IL-10 expression.
Understanding the molecular events governing cytokine expression will provide new treatment options in autoimmune disorders, including SLE. The observation that altered Stat3 activation enhances IL-10 expression in T cells offers a potential target in the search for novel biomarkers and treatment options in SLE.
A. P. Grammatikos,
N. Rodriguez Rodriguez,
V. C. Kyttaris,
J. C. Crispin,
G. C. Tsokos,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/stat3-promotes-il-10-expression-in-sle-t-cells-through-trans-activation-and-chromatin-remodeling/