Distinct mechanisms regulate IL1B gene transcription in lymphoid CD4 T cells and monocytes. (November 2018)

• Record Type: Journal Article
• Authors: Pulugulla, Sree H.; Packard, Thomas A.; Galloway, Nicole L.K.; Grimmett, Zachary W.; Doitsh, Gilad; Adamik, Juraj; Galson, Deborah L.; Greene, Warner C.; Auron, Philip E.
• Is Part Of: Cytokine. Volume 111(2018)
• Page Start: 373
• Page End: 381
• Publication Date: 2018-11
• Subjects: Spi1/PU.1 -- Interleukin 1beta -- Bivalent promoter -- T cell receptor activation; Cytokines -- Periodicals; 571.844
• DOI: 10.1016/j.cyto.2018.10.001
• Languages: English
• ISSNs: 1043-4666

Abstract

Graphical abstract: Highlights: TCR activation induces IL1B gene transcription in CD4 T cells. Unlike monocytes, IL1B in T cells is independent of critical myeloid Spi1 protein. Spi1 binding site on IL1B promoter is blocked by a nucleosome in CD4 T cells. Distinctly, IL1B gene in CD4 T cells utilizes a bivalent H3K4me3/H3k27me3 promoter. Abstract: Interleukin 1β is a pro-inflammatory cytokine important for both normal immune responses and chronic inflammatory diseases. The regulation of the 31 kDa proIL-1β precursor coded by the IL1B gene has been extensively studied in myeloid cells, but not in lymphoid-derived CD4 T cells. Surprisingly, we found that some CD4 T cell subsets express higher levels of proIL-1β than unstimulated monocytes, despite relatively low IL1B mRNA levels. We observed a significant increase in IL1B transcription and translation in CD4 T cells upon ex vivo CD3/CD28 activation, and a similar elevation in the CCR5+ effector memory population compared to CCR5− T cells in vivo . The rapid and vigorous increase in IL1B gene transcription for stimulated monocytes has previously been associated with the presence of Spi-1/PU.1 (Spi1), a myeloid-lineage transcription factor, pre-bound to the promoter. In the case of CD4 T cells, this increase occurred despite the lack of detectable Spi1 at the IL1B promoter. Additionally, we found altered epigenetic regulation of the IL1B locus in CD3/CD28–activated CD4 T cells. Unlike monocytes, activated CD4 T cells possess bivalent H3K4me3+/H3K27me3+ nucleosome marks at the IL1B promoter, reflecting low transcriptional activity. These results support a model in which the IL1B gene in CD4 T cells is transcribed from a low-activity bivalent promoter independent of Spi1. Accumulated cytoplasmic proIL-1β may ultimately be cleaved to mature 17 kDa bioactive IL-1β, regulating T cell polarization and pathogenic chronic inflammation.