Antagonism of IL-4 signaling by a phosphodiesterase-4 inhibitor, rolipram, in human T cells.
BACKGROUND
Phosphodiesterase (PDE4) inhibitors prevent breakdown of cAMP and affect the increase in cellular levels of cAMP, which is known to regulate immune cell functions. Because IL-4 plays a causal role in the pathogenesis of allergic disorders, we were interested to study the modulatory mechanisms of a PDE4 inhibitor, rolipram, in IL-4-mediated signaling in T cells.


METHODS
Human peripheral T cells were stimulated with IL-4 in combination with rolipram, and RT-PCR was performed using primers specific for IL-5. To monitor activation of transcription factors, immunostaining was employed.


RESULTS
Rolipram or a cAMP-analogue, 8-Br-cAMP, significantly downregulated IL-4-induced expression of IL-5 mRNA. The rolipram-induced inhibition of IL-5 mRNA was mediated by activation of protein kinase A (PKA), because rolipram-downregulated mRNA expression of IL-5 was restored by PKA inhibitors. Immunostaining revealed that rolipram interfered with IL-4-induced nuclear translocation of activator protein (AP)-1 components.


CONCLUSIONS
This is the first demonstration of suppression of IL-4 signaling by PDE4 inhibitors via prevention of nuclear translocation of AP-1.
Markova
Tzvetanka Petrova
TP
Department of Pharmacology, Kinki University School of Medicine, Osakasayama, Osaka, Japan.
Niwa
Atsuko
A
Yamanishi
Hiromichi
H
Aragane
Yoshinori
Y
Higashino
Hideaki
H
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015847:Interleukin-4 / Q000037:antagonists & inhibitors*; D015848:Interleukin-5 / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020889:Rolipram / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000378:metabolism
D015848:Interleukin-5; D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D015847:Interleukin-4; D015124:8-Bromo Cyclic Adenosine Monophosphate; D048049:Extracellular Signal-Regulated MAP Kinases; D020889:Rolipram