Regulatory Network Analyses Reveal Genome-Wide Potentiation of LIF Signaling by Glucocorticoids and Define an Innate Cell Defense Response

PLoS Genet. 2008 Oct;4(10):e1000224. doi: 10.1371/journal.pgen.1000224. Epub 2008 Oct 17.

Abstract

While the hypothalamo-pituitary-adrenal axis (HPA) activates a general stress response by increasing glucocorticoid (Gc) synthesis, biological stress resulting from infections triggers the inflammatory response through production of cytokines. The pituitary gland integrates some of these signals by responding to the pro-inflammatory cytokines IL6 and LIF and to a negative Gc feedback loop. The present work used whole-genome approaches to define the LIF/STAT3 regulatory network and to delineate cross-talk between this pathway and Gc action. Genome-wide ChIP-chip identified 3,449 STAT3 binding sites, whereas 2,396 genes regulated by LIF and/or Gc were found by expression profiling. Surprisingly, LIF on its own changed expression of only 85 genes but the joint action of LIF and Gc potentiated the expression of more than a thousand genes. Accordingly, activation of both LIF and Gc pathways also potentiated STAT3 and GR recruitment to many STAT3 targets. Our analyses revealed an unexpected gene cluster that requires both stimuli for delayed activation; 83% of the genes in this cluster are involved in different cell defense mechanisms. Thus, stressors that trigger both general stress and inflammatory responses lead to activation of a stereotypic innate cellular defense response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute-Phase Proteins / genetics
  • Animals
  • Binding Sites / genetics
  • Cell Line
  • Chromatin Immunoprecipitation
  • Dexamethasone / pharmacology
  • Feedback, Physiological
  • Gene Expression Profiling
  • Gene Regulatory Networks / drug effects
  • Genome
  • Glucocorticoids / metabolism
  • Glucocorticoids / pharmacology*
  • Hypothalamo-Hypophyseal System / drug effects
  • Hypothalamo-Hypophyseal System / physiology
  • Immunity, Innate
  • Leukemia Inhibitory Factor / genetics*
  • Leukemia Inhibitory Factor / immunology
  • Leukemia Inhibitory Factor / pharmacology
  • Leukemia Inhibitory Factor / physiology*
  • Lipocalin-2
  • Lipocalins / genetics
  • Mice
  • Multigene Family
  • Oncogene Proteins / genetics
  • Pituitary-Adrenal System / drug effects
  • Pituitary-Adrenal System / physiology
  • Receptors, Glucocorticoid / metabolism
  • Recombinant Proteins / pharmacology
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / immunology
  • STAT3 Transcription Factor / physiology
  • Signal Transduction / drug effects

Substances

  • Acute-Phase Proteins
  • Glucocorticoids
  • Leukemia Inhibitory Factor
  • Lif protein, mouse
  • Lipocalin-2
  • Lipocalins
  • Oncogene Proteins
  • Receptors, Glucocorticoid
  • Recombinant Proteins
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Lcn2 protein, mouse
  • Dexamethasone