ENHANCED TUMOR-NECROSIS-FACTOR SUPPRESSION AND CYCLIC ADENOSINE-MONOPHOSPHATE ACCUMULATION BY COMBINATION OF PHOSPHODIESTERASE INHIBITORS AND PROSTANOIDS

被引:85
作者
SINHA, B [1 ]
SEMMLER, J [1 ]
EISENHUT, T [1 ]
EIGLER, A [1 ]
ENDRES, S [1 ]
机构
[1] UNIV MUNICH, KLINIKUM INNENSTADT, MED KLIN, D-80336 MUNICH, GERMANY
关键词
TUMOR NECROSIS FACTOR; ADENYLATE CYCLASE ACTIVATORS; PHOSPHODIESTERASE INHIBITORS; ROLIPRAM; METHYLXANTHINES;
D O I
10.1002/eji.1830250125
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
We investigated cooperative effects of phosphodiesterase (PDE) inhibitors and prostanoids on cyclic adenosine monophosphate (cAMP) accumulation and tumor necrosis factor (TNF)-alpha synthesis in human peripheral blood mononuclear cells (PBMC). PDE inhibitors alone induced only a small increase in cAMP levels in lipopolysaccharide (LPS)-stimulated PBMC. Cicaprost (a stable analogue of prostacyclin) and pentoxifylline added simultaneously to LPS-stimulated PBMC (2.0 x 10(6)/ml) induced a rapid increase of cAMP to a level of 100 nM that peaked within 10 min and remained at a plateau for up to 4 h. Thus combined prostanoids and PDE inhibitors enhanced cAMP accumulation. TNF-alpha suppression in the presence of pentoxifylline and prostanoids exceeded that of either drug alone. The potency of different PDE inhibitors (theophylline, pentoxifylline, penthydroxifylline, albifylline, torbafylline, A 80 2715, amrinone and rolipram) to increase cAMP levels in combination with cicaprost was evaluated after 1 h of incubation. The dose-dependent increase of cAMP for all PDE inhibitors tested in this combined stimulation provided a useful tool for evaluating the potency of PDE inhibitors on cAMP accumulation. The effective concentration of PDE inhibitors, which raised cAMP levels to 300% of control, (EC(300)), correlated with the IC50 for TNF-alpha suppression (r = 0.930, p = 0.007, with theophylline excluded from the analysis). Interestingly, by contrast, the specific type IV PDE inhibitor rolipram caused only a moderate rise of accumulated cAMP in the same cells. Our data support cAMP as an essential mediator for TNF-alpha suppression by PDE inhibitors. Furthermore, an enhanced inhibiting effect on TNF-alpha production may prove therapeutically advantageous. It may occur in inflammatory and infectious diseases in vivo, since high levels of endogenous prostaglandins are liberated in these conditions.
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页码:147 / 153
页数:7
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