Phosphodiesterase 8 (PDE8) regulates chemotaxis of activated lymphocytes.
The immune system depends on chemokines to recruit lymphocytes to tissues in inflammatory diseases. This study identifies PDE8 as a new target for inhibition of chemotaxis of activated lymphocytes. Chemotactic responses of unstimulated and concanavalin A-stimulated mouse splenocytes and their modulation by agents that stimulate the cAMP signaling pathway were compared. Dibutyryl cAMP inhibited migration of both cell types. In contrast, forskolin and 3-isobutyl-1-methylxanthine each inhibited migration of unstimulated splenocytes, with little effect on migration of stimulated splenocytes. Only dipyridamole alone, a PDE inhibitor capable of inhibiting PDE8, strongly inhibited migration of stimulated and unstimulated splenocytes and this inhibition was enhanced by forskolin and reversed by a PKA antagonist. Following concanavalin A stimulation, mRNA for PDE8A1 was induced. These results suggest that in employing PDE inhibitor therapy for inflammatory illnesses, inhibition of PDE8 may be required to inhibit migration of activated lymphocytes to achieve a full therapeutic effect.
Dong
Hongli
H
Department of Pharmacology, University of Connecticut Health Center, Farmington, CT 06030-6125, USA.
Osmanova
Venera
V
Epstein
Paul M
PM
Brocke
Stefan
S
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D005576:Colforsin / Q000494:pharmacology; D003208:Concanavalin A / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004176:Dipyridamole / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy; D008213:Lymphocyte Activation / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger; D003208:Concanavalin A; D005576:Colforsin; D004176:Dipyridamole; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C520790:Pde8a protein, mouse; D015056:1-Methyl-3-isobutylxanthine