Abstract
Background: Abolishing the inhibitory signal of intracellular cAMP by phosphodiesterases (PDEs) is a prerequisite for
effector T (Teff) cell function. While PDE4 plays a prominent role, its control of cAMP levels in Teff cells is not exclusive. T cell
activation has been shown to induce PDE8, a PDE isoform with 40- to 100-fold greater affinity for cAMP than PDE4. Thus, we
postulated that PDE8 is an important regulator of Teff cell functions.
Methodology/Principal Findings: We found that Teff cells express PDE8 in vivo. Inhibition of PDE8 by the PDE inhibitor
dipyridamole (DP) activates cAMP signaling and suppresses two major integrins involved in Teff cell adhesion. Accordingly,
DP as well as the novel PDE8-selective inhibitor PF-4957325-00 suppress firm attachment of Teff cells to endothelial cells.
Analysis of downstream signaling shows that DP suppresses proliferation and cytokine expression of Teff cells from Crem2/2
mice lacking the inducible cAMP early repressor (ICER). Importantly, endothelial cells also express PDE8. DP treatment
decreases vascular adhesion molecule and chemokine expression, while upregulating the tight junction molecule claudin-5.
In vivo, DP reduces CXCL12 gene expression as determined by in situ probing of the mouse microvasculature by cellselective laser-capture microdissection.
Conclusion/Significance: Collectively, our data identify PDE8 as a novel target for suppression of Teff cell functions,
including adhesion to endothelial cells.
effector T (Teff) cell function. While PDE4 plays a prominent role, its control of cAMP levels in Teff cells is not exclusive. T cell
activation has been shown to induce PDE8, a PDE isoform with 40- to 100-fold greater affinity for cAMP than PDE4. Thus, we
postulated that PDE8 is an important regulator of Teff cell functions.
Methodology/Principal Findings: We found that Teff cells express PDE8 in vivo. Inhibition of PDE8 by the PDE inhibitor
dipyridamole (DP) activates cAMP signaling and suppresses two major integrins involved in Teff cell adhesion. Accordingly,
DP as well as the novel PDE8-selective inhibitor PF-4957325-00 suppress firm attachment of Teff cells to endothelial cells.
Analysis of downstream signaling shows that DP suppresses proliferation and cytokine expression of Teff cells from Crem2/2
mice lacking the inducible cAMP early repressor (ICER). Importantly, endothelial cells also express PDE8. DP treatment
decreases vascular adhesion molecule and chemokine expression, while upregulating the tight junction molecule claudin-5.
In vivo, DP reduces CXCL12 gene expression as determined by in situ probing of the mouse microvasculature by cellselective laser-capture microdissection.
Conclusion/Significance: Collectively, our data identify PDE8 as a novel target for suppression of Teff cell functions,
including adhesion to endothelial cells.
| Original language | English |
|---|---|
| Article number | e12011 |
| Pages (from-to) | 1-13 |
| Number of pages | 13 |
| Journal | PloS one |
| Volume | 5 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - Aug 2010 |