Differential regulation of human antigen-specific Th1 and Th2 lymphocyte responses by isozyme selective cyclic nucleotide phosphodiesterase inhibitors

David M. Essayan, Anne Kagey-Sobotka, Lawrence M. Lichtenstein, Shau Ku Huang

Research output: Contribution to journalArticle

Abstract

Our study explores the relative efficacy of phosphodiesterase (PDE) inhibitors on antigen-specific Th1 and Th2 clonal responses. Proliferative responses for both phenotypes were down-regulated by the PDE4 inhibitor, rolipram, but not the PDE3 inhibitor, siguazodan. The Th2 clones were more sensitive than the Th1 clones to PDE4 inhibition (P <.05 at 10 and 100 μM rolipram). The addition of 1 μM of the adenylyl cyclace activator, isoproterenol, significantly decreased both the EC50 and IC50 of rolipram in both phenotypes (P <.05). Gene expression for interleukin-4, interleukin- 5, or interferon-γ, assessed by reverse transcription-polymerase chain reaction, was down-regulated by the PDE4 inhibitor, but not the PDE3 inhibitor, in each respective clone. Cytokine protein secretion paralleled the results of reverse transcription-polymerase chain reaction for IL-4 and interferon-γ (P <.01 for each). No differential efficacy on cytokine generation parameters between T helper phenotypes was apparent. Rolipram treatment significantly elevated intracellular cyclic AMP (adenosine 3',5'- cyclic monophosphate) in clonal T cells (P <.01 for Th1 or Th2 clones); these elevations were consistently greater in the Th2 clones (P <.05). Finally, Th1 cells showed reduced gene expression for the PDE4C isoform and a lack of gene expression for the PDE4D isoform by reverse transcription- polymerase chain reaction, compared to the Th2 cells. These data demonstrate the potent immunomodulatory efficacy of PDE4 inhibition on antigen-specific T cell clones. The enhanced sensitivity of Th2 cells to PDE4 inhibition may be due, in part, to the differential expression of PDE4 isoforms between Th1 and Th2 cells.

Original languageEnglish (US)
Pages (from-to)505-512
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume282
Issue number1
Publication statusPublished - Jul 1997

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ASJC Scopus subject areas

  • Pharmacology

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