Phosphodiesterase 4B negatively regulates endotoxin-activated interleukin-1 receptor antagonist responses in macrophages

Sci Rep. 2017 Apr 6;7:46165. doi: 10.1038/srep46165.

Abstract

Activation of TLR4 by lipopolysaccharide (LPS) induces both pro-inflammatory and anti-inflammatory cytokine production in macrophages. Type 4 phosphodiesterases (PDE4) are key cAMP-hydrolyzing enzymes, and PDE4 inhibitors are considered as immunosuppressors to various inflammatory responses. We demonstrate here that PDE4 inhibitors enhance the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1Ra) secretion in LPS-activated mouse peritoneal macrophages, and this response was regulated at the transcriptional level rather than an increased IL-1Ra mRNA stability. Studies with PDE4-deficient macrophages revealed that the IL-1Ra upregulation elicited by LPS alone is PKA-independent, whereas the rolipram-enhanced response was mediated by inhibition of only PDE4B, one of the three PDE4 isoforms expressed in macrophages, and it requires PKA but not Epac activity. However, both pathways activate CREB to induce IL-1Ra expression. PDE4B ablation also promoted STAT3 phosphorylation (Tyr705) to LPS stimulation, but this STAT3 activation is not entirely responsible for the IL-1Ra upregulation in PDE4B-deficient macrophages. In a model of LPS-induced sepsis, only PDE4B-deficient mice displayed an increased circulating IL-1Ra, suggesting a protective role of PDE4B inactivation in vivo. These findings demonstrate that PDE4B negatively modulates anti-inflammatory cytokine expression in innate immune cells, and selectively targeting PDE4B should retain the therapeutic benefits of nonselective PDE4 inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Survival / drug effects
  • Cyclic AMP / metabolism
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / deficiency
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism*
  • Interleukin 1 Receptor Antagonist Protein / blood
  • Interleukin 1 Receptor Antagonist Protein / genetics
  • Interleukin 1 Receptor Antagonist Protein / metabolism*
  • Interleukin-1beta / blood
  • Lipopolysaccharides / pharmacology*
  • Macrophages, Peritoneal / drug effects
  • Macrophages, Peritoneal / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Phosphodiesterase 4 Inhibitors / pharmacology
  • Phosphorylation / drug effects
  • RAW 264.7 Cells
  • RNA Stability / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rolipram / pharmacology
  • STAT3 Transcription Factor / metabolism
  • Sepsis / blood
  • Sepsis / pathology
  • Signal Transduction / drug effects
  • Up-Regulation / drug effects

Substances

  • Cyclic AMP Response Element-Binding Protein
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1beta
  • Lipopolysaccharides
  • Phosphodiesterase 4 Inhibitors
  • RNA, Messenger
  • STAT3 Transcription Factor
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Rolipram