Inhibition of phosphodiesterase 4 amplifies cytokine-dependent induction of arginase in macrophages

Aaron Erdely, Diane Kepka-Lenhart, Melissa Clark, Patti Zeidler-Erdely, Mirjana Poljakovic, William J. Calhoun, Sidney M. Morris

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

Arginase is greatly elevated in asthma and is thought to play a role in the pathophysiology of this disease. As inhibitors of phosphodiesterase 4 (PDE4), the predominant PDE in macrophages, elevate cAMP levels and reduce inflammation, they have been proposed for use in treatment of asthma and chronic obstructive pulmonary disease. As cAMP is an inducer of arginase, we tested the hypothesis that a PDE4 inhibitor would enhance macrophage arginase induction by key cytokines implicated in asthma and other pulmonary diseases. RAW 264.7 cells were stimulated with IL-4 or transforming growth factor (TGF)-β, with and without the PDE4 inhibitor rolipram. IL-4 and TGF-β increased arginase activity 16- and 5-fold, respectively. Rolipram alone had no effect but when combined with IL-4 and TGF-β synergistically enhanced arginase activity by an additional 15- and 5-fold, respectively. The increases in arginase I protein and mRNA levels mirrored increases in arginase activity. Induction of arginase II mRNA was also enhanced by rolipram but to a much lesser extent than arginase I. Unlike its effect in RAW 264.7 cells, IL-4 alone did not increase arginase activity in human alveolar macrophages (AM) from healthy volunteers. However, combining IL-4 with agents to induce cAMP levels induced arginase activity in human AM significantly above the level obtained with cAMP-inducing agents alone. In conclusion, agents that elevate cAMP significantly enhance induction of arginase by cytokines. Therefore, consequences of increased arginase expression should be evaluated whenever PDE inhibitors are proposed for treatment of inflammatory disorders in which IL-4 and/or TGF-β predominate.

Original languageEnglish (US)
Pages (from-to)L534-L539
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume290
Issue number3
DOIs
StatePublished - Mar 2006

Keywords

  • Adenosine 3′,5′-cyclic monophosphate
  • Interleukin-4
  • Nitric oxide
  • Real-time reverse transcriptase polymerase chain reaction
  • Transforming growth factor-β

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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