Differential regulation of human antigen-specific Th1 and Th2 lymphocyte responses by isozyme selective cyclic nucleotide phosphodiesterase inhibitors.
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 microM rolipram). The addition of 1 microM 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-gamma, 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-gamma (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.
Essayan
D M
DM
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, USA.
Kagey-Sobotka
A
A
Lichtenstein
L M
LM
Huang
S K
SK
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000242:Cyclic AMP / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008213:Lymphocyte Activation / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology; D020889:Rolipram; D018417:Th1 Cells / Q000187:drug effects* / Q000502:physiology; D018418:Th2 Cells / Q000187:drug effects* / Q000502:physiology
D016207:Cytokines; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D020889:Rolipram