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Quantification of Monocyte Chemotactic Activity In Vivo and Characterization of Blood Monocyte Derived Macrophages
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Quantification of Monocyte Chemotactic Activity In Vivo and Characterization of Blood Monocyte Derived Macrophages

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Elevated cyclic AMP and PDE4 inhibition induce chemokine expression in human monocyte-derived macrophages

Angie L Hertz1, Andrew T Bender, Kimberly C Smith

  • 1Department of Pharmacology, University of Washington Medical School, Seattle, WA 98195, USA.

Proceedings of the National Academy of Sciences of the United States of America
|December 5, 2009
PubMed

Insights

Elevated cyclic adenosine monophosphate (cAMP) levels during monocyte differentiation increase pro-inflammatory chemokines via Epac. PDE4 inhibitors potentiate this effect, suggesting combination therapy for inflammatory disorders.

Area of Science:

  • Immunology
  • Cell Biology

Background:

  • Macrophages are key innate immune cells differentiated from monocytes.
  • Elevated cyclic adenosine monophosphate (cAMP) generally inhibits macrophage inflammatory responses.
  • The impact of increased cAMP on monocyte/macrophage differentiation remains less understood.

Purpose of the Study:

  • To investigate the effect of elevated cAMP on monocyte/macrophage differentiation.
  • To identify the role of Epac (cAMP-activated exchange protein) in this process.
  • To explore the potential of phosphodiesterase 4 (PDE4) inhibitors in modulating chemokine expression.

Main Methods:

  • Monocyte differentiation was induced with cytokine exposure.
  • cAMP agonists were used to elevate intracellular cAMP levels.
  • mRNA and protein levels of chemokines (CXCL, CCL) were quantified.
  • The role of Epac was assessed using specific mediators.
  • The effect of a PDE4 inhibitor on chemokine expression was evaluated.

Main Results:

  • Elevated cAMP during differentiation significantly increased mRNA and protein levels of pro-inflammatory chemokines (CXCL, CCL).
  • Epac was found to substantially contribute to the cAMP-induced increase in chemokine expression.
  • A selective PDE4 inhibitor potentiated chemokine expression induced by low-dose forskolin or Prostaglandin E2 (PGE(2)).

Conclusions:

  • Increased cAMP during monocyte differentiation promotes the expression of pro-inflammatory chemokines, partly mediated by Epac.
  • PDE4 inhibitors can enhance this chemokine response.
  • Combination therapy with chemokine receptor antagonists and PDE4 inhibitors may offer improved efficacy and safety for inflammatory diseases like asthma and COPD.

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