Cyclic nucleotides differentially regulate the synthesis of tumour necrosis factor-α and interleukin-1β by human mononuclear cells.

Recent reports have shown that phosphodiesterase (PDE) inhibitors suppress production of tumour necrosis factor-alpha (TNF-α) in mouse macrophages. In the present study we show that theophylline, pentoxifylline and 3-isobutyl-1-methylxanthine markedly suppress the lipopolysaccharide (LPS)-induced synthesis of TNF-α (also) in human mononuclear cells. This effect is selective for TNF-α since up to several-fold higher concentrations of these PDE inhibitors do not affect production of interleukin-1β (IL-1β) in the same system. The observed effect of PDE inhibitors appears to be mediated by accumulation of cAMP since (i) addition of PDE inhibitors increases cAMP while cGMP levels are only marginally elevated; (ii) raising cAMP by another mechanism (enhanced formation induced by prostaglandin E₂; PGE₂) leads to a similar suppression of TNF-α production; and (iii) raising cGMP by activating the soluble guanylate cyclase by 3-morpholinosydnonimine (SIN 1) does not inhibit TNF-α synthesis. However, SIN 1 suppressed the synthesis of IL-1β. Selective suppression of TNF-α synthesis by PDE inhibitors may contribute to their beneficial effects in animal models of septic shock or lung injury and may thus have clinical implications. [ABSTRACT FROM AUTHOR]