PDE8 regulates rapid Teff cell adhesion and proliferation independent of ICER.
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.


RESULTS
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 Crem-/- 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 cell-selective laser-capture microdissection.


CONCLUSIONS
Collectively, our data identify PDE8 as a novel target for suppression of Teff cell functions, including adhesion to endothelial cells.
Vang
Amanda G
AG
Department of Immunology, University of Connecticut Health Center, Farmington, Connecticut, United States of America.
Ben-Sasson
Shlomo Z
SZ
Dong
Hongli
H
Kream
Barbara
B
DeNinno
Michael P
MP
Claffey
Michelle M
MM
Housley
William
W
Clark
Robert B
RB
Epstein
Paul M
PM
Brocke
Stefan
S
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000235:genetics; D062507:Claudin-5; D000242:Cyclic AMP / Q000378:metabolism; D051786:Cyclic AMP Response Element Modulator / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D004176:Dipyridamole / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006868:Hydrolysis; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
D054377:Chemokine CXCL12; D062507:Claudin-5; C491511:Cldn5 protein, mouse; D016207:Cytokines; D008565:Membrane Proteins; D010726:Phosphodiesterase Inhibitors; D051786:Cyclic AMP Response Element Modulator; D004176:Dipyridamole; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C543000:PDE4B protein, mouse; C520790:Pde8a protein, mouse