Modulation of TNF alpha and IL-1 beta from endotoxin-stimulated monocytes by selective PDE isozyme inhibitors.
The effect of selective PDE isozyme inhibitors including vinpocetine (PDE-I), CI-930 and milrinone (PDE-III), rolipram and nitraquazone (PDE-IV) and zaprinast (PDE-V) on monocyte viability and production of tumor necrosis factor (TNF alpha) and interleukin-1 beta (IL-1 beta) elicited from endotoxin-stimulated human monocytes was investigated. None of the inhibitors affected monocyte viability at 10 microM or lower concentrations. PDE-IV inhibitors and to a lesser extent, PDE-III inhibitors suppressed TNF alpha production. Only high concentrations of PDE-IV inhibitors modestly suppressed IL-1 beta. Zaprinast stimulated IL-1 beta and to a lesser extent TNF alpha production. These data show that TNF alpha and IL-1 beta production are differentially regulated, and that PDE III, PDE-IV and PDE-V isozymes are functional in endotoxin-stimulated monocytes. Clinical trials will be needed to ascertain if PDE-IV inhibitors are able to suppress TNF alpha levels in man.
Molnar-Kimber
K
K
Wyeth-Ayerst Research, Princeton, NJ 08453-8000.
Yonno
L
L
Heaslip
R
R
Weichman
B
B
D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004731:Endotoxins / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism*; D007527:Isoenzymes; D020105:Milrinone; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011688:Purinones / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D020889:Rolipram; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014748:Vinca Alkaloids / Q000494:pharmacology
D004731:Endotoxins; D007375:Interleukin-1; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D011728:Pyridones; D011760:Pyrrolidinones; D011799:Quinazolines; D014409:Tumor Necrosis Factor-alpha; D014748:Vinca Alkaloids; C044248:nitraquazone; C013983:vinpocetine; C011145:zaprinast; D020105:Milrinone; D020889:Rolipram