Stat3 and Stat5 govern IL-10 expression in T cells through trans-activation and epigenetic remodelling in health and disease

Abstract

IL-10 is an immune-regulatory cytokine that plays a central role during innate and adaptive immune responses. T cells are a major source of IL-10. The molecular mechanisms governing IL-10 expression remain only partially understood. The autoimmune disorder systemic lupus erythematosus (SLE) is characterized by autoantibody production, immune complex formation, and altered cytokine expression. IL-10 is elevated in the serum and tissues of SLE patients. Next to its anti-inflammatory capacities, IL-10 promotes the differentiation, survival, and activity of B cells. Thus, IL-10 contributes to autoantibody production and tissue damage in SLE. The molecular events contributing to the increased expression of IL-10 in SLE patients remain to be determined. We aimed to determine molecular mechanisms controlling IL10 in health and disease. In T cells, DNA methylation of the IL10 promoter and the 4th intron governs the recruitment of Stat transcription factors. Both Stat3 and Stat5, which are recruited to the 5’ proximal promoter and the 4th intron, regulate IL-10. Stat3 and Stat5 mediate both trans-activation and epigenetic remodelling through their interaction with the histone acetyltransferase p300. In T cells from SLE patients, activation of Stat3 is increased, resulting in a replacement of Stat5, subsequently promoting IL-10 expression. Understanding the molecular events contributing to cytokine deregulation in SLE will offer new therapeutic options. Correcting the imbalanced activation of Stat transcription factors may be a promising candidate in the search for novel therapeutic approaches in SLE.