Effects of cAMP-phosphodiesterase isozyme inhibitor on cytokine production by lipopolysaccharide-stimulated human peripheral blood mononuclear cells.
1. The effects of cAMP-phosphodiesterase (PDE) isozyme inhibitors on the production of tumor necrosis factor alpha (TNF-alpha), and interleukins 1 beta 8 (IL-1 beta and IL-8) by lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells (PBMC) were evaluated. In addition, we investigated the effects of dibutyryl cAMP (dbcAMP) and beta-adrenergic receptor agonist on the production of these cytokines. 2. Type IV PDE inhibitors were more effective at inhibiting the production of TNF-alpha and IL-1 beta by LPS-stimulated PBMC than a nonselective, type III or type III/IV inhibitor. In contrast, these agents had no effect on IL-8 production. 3. Increasing concentrations of dbcAMP progressively reduced the production of TNF-alpha and IL-1 beta but not IL-8. 4. The addition of beta-agonist increased the inhibitory effect of PDE inhibitors tested on the production of TNF-alpha and IL-1 beta. 5. Type IV PDE inhibitors could be potent pharmacological agents for the treatment of diseases in which TNF-alpha and IL-1 beta are important etiological factors.
Yoshimura
T
T
Pharmaceutical Division, Ogaki Municipal Hospital, Gifu, Japan.
Kurita
C
C
Nagao
T
T
Usami
E
E
Nakao
T
T
Watanabe
S
S
Kobayashi
J
J
Yamazaki
F
F
Tanaka
H
H
Nagai
H
H
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / Q000494:pharmacology; D000628:Aminophylline / Q000494:pharmacology; D003994:Bucladesine / Q000494:pharmacology; D016207:Cytokines / Q000097:blood*; D006801:Humans; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020105:Milrinone; D009287:Naphthyridines / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011688:Purinones / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D020889:Rolipram; D013726:Terbutaline / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016207:Cytokines; D007375:Interleukin-1; D016209:Interleukin-8; D007527:Isoenzymes; D008070:Lipopolysaccharides; D009287:Naphthyridines; D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D011728:Pyridones; D011760:Pyrrolidinones; D014409:Tumor Necrosis Factor-alpha; C073029:SDZ MKS 492; D000628:Aminophylline; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; D003994:Bucladesine; C044843:AH 21-132; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D020105:Milrinone; D020889:Rolipram; D013726:Terbutaline