TNF MODULATES ENDOTHELIAL PROPERTIES BY DECREASING CAMP

被引:103
作者
KOGA, S
MORRIS, S
OGAWA, S
LIAO, H
BILEZIKIAN, JP
CHEN, G
THOMPSON, WJ
ASHIKAGA, T
BRETT, J
STERN, DM
PINSKY, DJ
机构
[1] COLUMBIA UNIV, COLL PHYS & SURG, DEPT PHYSIOL, NEW YORK, NY 10032 USA
[2] COLUMBIA UNIV, COLL PHYS & SURG, DEPT MED, NEW YORK, NY 10032 USA
[3] UNIV SO ALABAMA, COLL MED, DEPT PHARMACOL, MOBILE, AL 36617 USA
来源
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY | 1995年 / 268卷 / 05期
关键词
TUMOR NECROSIS FACTOR; ENDOTHELIAL CELL; PERMEABILITY; ADENOSINE; 3'; 5'-CYCLIC MONOPHOSPHATE; THROMBOMODULIN; PHOSPHODIESTERASE;
D O I
10.1152/ajpcell.1995.268.5.C1104
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Tumor necrosis factor-alpha (TNF-alpha), a monokine that contributes to vascular dysfunction accompanying the host response to gram-negative sepsis, has been shown to increase vascular permeability in vivo and to diminish the barrier function of cultured endothelial cell (EC) monolayers. The studies reported here indicate that a mechanism through which TNF alters EC barrier function involves a reduction in intracellular adenosine 3',5'-cyclic monophosphate (cAMP) content, due in part to increased cyclic nucleotide phosphodiesterase (CNPDE) activities. TNF increased the diffusional transit of [H-3]sorbitol, [H-3]inulin, and I-125-labeled albumin across confluent bovine aortic EC monolayers. This effect of TNF was both time and dose dependent and occurred in parallel with a fall in EC cAMP. cAMP analogues, such as dibutyryl cAMP (DBcAMP), prevented TNF-induced perturbation of EC barrier function. TNF also mediated another important alteration in the EC phenotype, in that both mRNA and activity of the anticoagulant cofactor thrombomodulin were reduced after exposure of EC to TNF and were normalized by the addition of DBcAMP. EC monolayers exposed to TNF-alpha showed increased cAMP levels when exposed to S-isobutyl-1-methylxanthine, a nonspecific CNPDE inhibitor. Ion exchange chromatography of cytosol derived from TNF-treated EC consistently showed an similar to 245% increase in phosphodiesterase (PDE) IV (high-affinity, cAMP-specific PDE) activity as identified by rolipram inhibition. PDE II activity was increased by 150% after TNF-alpha treatment of early passage EC, which was identified by cGMP-activated hydrolysis of cAMP. Western and Northern analyses, as well as activity studies, revealed that TNF treatment did not change the amount of PDE TV protein or mRNA but rather increased the specific activity of the isozyme, suggesting that a posttranslational modification had occurred. These data indicate that activation of EC CNPDE activity and decreased intracellular cAMP may represent a mechanism by which TNF increases EC permeability and promotes a procoagulant EC phenotype.
引用
收藏
页码:C1104 / C1113
页数:10
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