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Vol. 282, Issue 1, 505-512, 1997
Division of Clinical Immunology, Department of Medicine, Johns
Hopkins University School of Medicine, Baltimore, Maryland
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 cyclase 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-
, 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-
(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.
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