A biochemical and functional assessment of monocyte phosphodiesterase activity in healthy and asthmatic subjects.
The aim of this study was to investigate whether cyclic adenosine 3'5-monophosphate (cAMP) phosphodiesterase (PDE) activity is altered in monocytes from mild asthmatic subjects. Total cAMP PDE activity (pmol/min per mg protein) was significantly greater in homogenates prepared from monocytes from asthmatic subjects (68.3 +/- 7.0, n=9) compared to healthy individuals (46.3 +/- 3.3, n=14, P<0.05). The PDE inhibitors siguazodan (PDE3-selective), rolipram (PDE4-selective) and theophylline (non-selective) produced a concentration-dependent inhibition of cAMP PDE activity in homogenates from monocytes from normal and asthmatic subjects. However, siguazodan produced significantly greater (P<0.05), and rolipram significantly less (P<0.05), inhibition of total cAMP PDE activity in monocytes from asthmatics (n=4) than from healthy individuals (n=5). cAMP PDE activity was inhibited with equal potency by theophylline in monocytes from healthy and asthmatic subjects. We also investigated the functional consequences of the changes in PDE activity in mononuclear cells obtained from asthmatic subjects. There was no significant difference in the ability of PDE4 inhibitors to attenuate TNF alpha release from monocytes obtained from asthmatic compared with healthy subjects (P>0.05). Despite a significant increase in the biochemical activity of PDE3 in monocytes from asthmatic subjects, the PDE3 inhibitor siguazodan, failed to significantly reduce TNF alpha release from human monocytes. Thus, total cAMP PDE activity is increased in monocytes taken from mild asymptomatic asthmatics compared to healthy subjects and is reflected by an increase in the proportion of PDE3 and a decrease in the proportion of PDE4. This augmented enzyme activity was not associated with an alteration in the ability of PDE4 inhibitors to attenuate mononuclear cell function from asthmatics compared to healthy individuals.
Landells
L J
LJ
Sackler Institute of Pulmonary Pharmacology, Division of Pharmacology and Therapeutics, London, SE1 9RT, UK.
Spina
D
D
Souness
J E
JE
O'Connor
B J
BJ
Page
C P
CP
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000328:Adult; D000368:Aged; D001249:Asthma / Q000188:drug therapy / Q000201:enzymology*; D016022:Case-Control Studies; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology; D020889:Rolipram / Q000494:pharmacology; D013806:Theophylline / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D006146:Guanidines; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D014409:Tumor Necrosis Factor-alpha; C056215:siguazodan; D013806:Theophylline; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D020889:Rolipram