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 (TNFalpha) and interleukin-1beta (IL-1beta) elicited from endotoxin-stimulated human monocytes was investigated. None of the inhibitors affected monocyte viability at 10 muM or lower concentrations. PDE-IV inhibitors and to a lesser extent, PDE-III inhibitors suppressed TNFalpha production. Only high concentrations of PDE-IV inhibitors modestly suppressed IL-1beta. Zaprinast stimulated IL-1beta and to a lesser extent TNFalpha production. These data show that TNFalpha and IL-1beta 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 TNFalpha levels in man.