Mitochondrial Membrane Potential Regulates Nuclear Gene Expression in Macrophages Exposed to Prostaglandin E2

Immunity. 2018 Dec 18;49(6):1021-1033.e6. doi: 10.1016/j.immuni.2018.10.011.


Metabolic engagement is intrinsic to immune cell function. Prostaglandin E2 (PGE2) has been shown to modulate macrophage activation, yet how PGE2 might affect metabolism is unclear. Here, we show that PGE2 caused mitochondrial membrane potential (Δψm) to dissipate in interleukin-4-activated (M(IL-4)) macrophages. Effects on Δψm were a consequence of PGE2-initiated transcriptional regulation of genes, particularly Got1, in the malate-aspartate shuttle (MAS). Reduced Δψm caused alterations in the expression of 126 voltage-regulated genes (VRGs), including those encoding resistin-like molecule α (RELMα), a key marker of M(IL-4) cells, and genes that regulate the cell cycle. The transcription factor ETS variant 1 (ETV1) played a role in the regulation of 38% of the VRGs. These results reveal ETV1 as a Δψm-sensitive transcription factor and Δψm as a mediator of mitochondrial-directed nuclear gene expression.

Keywords: ETS variant 1; ETV1; IL-4; PGE2; RELMα; immunometabolism; interleukin-4; macrophage; malate-aspartate shuttle; mitochondria; mitochondrial membrane potential; proliferation; prostaglandin E2.

Publication types

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

MeSH terms

  • Animals
  • Cell Nucleus / drug effects*
  • Cell Nucleus / genetics
  • Cells, Cultured
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Dinoprostone / pharmacology*
  • Gene Expression Profiling
  • Gene Expression Regulation / drug effects*
  • HEK293 Cells
  • Humans
  • Interleukin-4 / pharmacology
  • Macrophage Activation / drug effects
  • Macrophage Activation / genetics
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • Macrophages / ultrastructure
  • Membrane Potential, Mitochondrial / physiology*
  • Mice
  • Mice, Inbred C57BL
  • NIH 3T3 Cells
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Transcription Factors / genetics
  • Transcription Factors / metabolism


  • DNA-Binding Proteins
  • Etv1 protein, mouse
  • Transcription Factors
  • Interleukin-4
  • Dinoprostone