Stat3 promotes IL-10 expression in lupus T cells through trans- activation and chromatin remodeling

Abstract

The immune-regulatory cytokine IL-10 plays a central role during innate and adaptive immune responses. IL-10 is elevated in the serum and tissues of patients with systemic lupus erythematosus (SLE), an autoimmune disorder characterized by autoantibody production, immune-complex formation, and altered cytokine expression. Because of its B cell-promoting effects, IL-10 may contribute to autoantibody production and tissue damage in SLE. We aimed to determine molecular events governing T cell-derived IL-10 expression in health and disease. We link reduced DNA methylation of the IL10 gene with increased recruitment of Stat family transcription factors. Stat3 and Stat5 recruitment to the IL10 promoter and an intronic enhancer regulate gene expression. Both Stat3 and Stat5 mediate trans-activation and epigenetic remodeling of IL10 through their interaction with the histone acetyltransferase p300. In T cells from SLE patients, activation of Stat3 is increased, resulting in enhanced recruitment to regulatory regions and competitive replacement of Stat5, subsequently promoting IL-10 expression. A complete understanding of the molecular events governing cytokine expression will provide new treatment options in autoimmune disorders, including SLE. The observation that altered activation of Stat3 influences IL-10 expression in T cells from SLE patients offers molecular targets in the search for novel target-directed treatment options.

Apoptotic cell-derived membrane microparticles and IFN-α induce an inflammatory immune response

“…Recent studies have suggested an involvement of several members of the STAT family in the pathogenesis of SLE (Hedrich et al, 2014;Huang et al, 2011). STAT1 in particular has been associated with the development of, for example, lupus nephritis (Dong et al, 2007) and purpose anaemia (DominguezGutierrez et al, 2014) and also has been shown to be hypomethylated in CD4+ T-cells from lupus patients (Coit et al, 2013) as well as having higher expression in peripheral blood mononuclear cells (PBMCs) from SLE patients (Karonitsch et al, 2009).…”

Histone H1 and Chromosomal Protein HMGN2 Regulate Prolactin-induced STAT5 Transcription Factor Recruitment and Function in Breast Cancer Cells

“…Correspondingly, mammary-specific genes have been shown to exhibit an open chromatin organization that is specific not just to mammary tissue but also to the appropriate developmental stage (28). One study has shown that DNA methylation in particular is associated with impaired STAT5 recruitment (29). However, additional chromatin-remodeling events that enable or prevent STAT5 recruitment have not been well characterized.…”

T cell signaling abnormalities contribute to aberrant immune cell function and autoimmunity

“…Besides its proinflammatory role, IL-17 also activates anti-dsDNA antibody production, as evidenced by high antibody production in PBMCs from patients with lupus nephritis (63). Lastly, epigenetic modifications invoked by STAT3 appear to account for the increased production of IL-10 in patients with SLE (64,65). Mice overexpressing CREMα in T cells predictably produce less IL-2 (66) and interestingly produce more IL-17.…”

“…A number of cytokine genes are overexpressed in CD4 + T cells in a chromatin-dependent manner including IL4, IL10, IL13, and IL17 (64). Recently it has been shown that the IL10 gene is hypomethylated in SLE T cells and allows for chromatin remodeling and p-STAT3 recruitment to its promoter to increase IL-10 expression (65). The promoter of the serine/threonine phosphatase PP2A is hypomethylated, resulting in its overexpression and aberrant activity in T cells from SLE patients (97).…”