Distinct Mechanisms Regulate IL1B Gene Transcription in Lymphoid CD4 T Cells and Monocytes

Cytokine. 2018 Nov;111:373-381. doi: 10.1016/j.cyto.2018.10.001. Epub 2018 Oct 6.

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.

Keywords: Bivalent promoter; Interleukin 1beta; Spi1/PU.1; T cell receptor activation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers / metabolism
  • CD28 Antigens / genetics
  • CD3 Complex / genetics
  • CD4-Positive T-Lymphocytes / physiology*
  • Epigenesis, Genetic / genetics
  • Gene Expression Regulation / genetics
  • Humans
  • Interleukin-1beta / genetics*
  • Monocytes / physiology*
  • Nucleosomes / genetics
  • Promoter Regions, Genetic / genetics
  • Proto-Oncogene Proteins / genetics
  • RNA, Messenger / genetics
  • Receptors, CCR5 / genetics
  • Transcription, Genetic / genetics*
  • Transcriptional Activation / genetics

Substances

  • Biomarkers
  • CD28 Antigens
  • CD3 Complex
  • Interleukin-1beta
  • Nucleosomes
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Receptors, CCR5