Glucocorticoid and cytokine crosstalk: Feedback, feedforward, and co-regulatory interactions determine repression or resistance

J Biol Chem. 2017 Apr 28;292(17):7163-7172. doi: 10.1074/jbc.R117.777318. Epub 2017 Mar 10.

Abstract

Inflammatory signals induce feedback and feedforward systems that provide temporal control. Although glucocorticoids can repress inflammatory gene expression, glucocorticoid receptor recruitment increases expression of negative feedback and feedforward regulators, including the phosphatase, DUSP1, the ubiquitin-modifying enzyme, TNFAIP3, or the mRNA-destabilizing protein, ZFP36. Moreover, glucocorticoid receptor cooperativity with factors, including nuclear factor-κB (NF-κB), may enhance regulator expression to promote repression. Conversely, MAPKs, which are inhibited by glucocorticoids, provide feedforward control to limit expression of the transcription factor IRF1, and the chemokine, CXCL10. We propose that modulation of feedback and feedforward control can determine repression or resistance of inflammatory gene expression toglucocorticoid.

Keywords: gene expression; gene regulation; glucocorticoid; glucocorticoid receptor; inflammation.

Publication types

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

MeSH terms

  • A549 Cells
  • Animals
  • Chemokine CXCL10 / metabolism
  • Cytokines / metabolism*
  • Dual Specificity Phosphatase 1 / metabolism
  • Feedback, Physiological
  • Gene Expression Regulation
  • Gene Expression Regulation, Neoplastic
  • Glucocorticoids / metabolism*
  • Humans
  • Inflammation
  • Interferon Regulatory Factor-1 / metabolism
  • MAP Kinase Signaling System
  • Mice
  • NF-kappa B / metabolism
  • RNA, Messenger / metabolism
  • Receptors, Glucocorticoid / metabolism
  • Signal Transduction*
  • Transcription Factor RelA / metabolism
  • Tristetraprolin / metabolism
  • Tumor Necrosis Factor alpha-Induced Protein 3 / metabolism

Substances

  • CXCL10 protein, human
  • Chemokine CXCL10
  • Cytokines
  • Glucocorticoids
  • IRF1 protein, human
  • Interferon Regulatory Factor-1
  • NF-kappa B
  • RELA protein, human
  • RNA, Messenger
  • Receptors, Glucocorticoid
  • Transcription Factor RelA
  • Tristetraprolin
  • ZFP36 protein, human
  • DUSP1 protein, human
  • Dual Specificity Phosphatase 1
  • TNFAIP3 protein, human
  • Tumor Necrosis Factor alpha-Induced Protein 3