TNF modulates endothelial properties by decreasing cAMP

S. Koga, S. Morris, S. Ogawa, H. Liao, J. P. Bilezikian, G. Chen, W. J. Thompson, T. Ashikaga, J. Brett, David Stern, D. J. Pinsky

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Abstract

Tumor necrosis factor-α (TNF-α), 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 [ 3 H]sorbitol, [ 3 H]inulin, and 125 I-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-α showed increased cAMP levels when exposed to 3- isobutyl-1-methylxanthine, a nonspecific CNPDE inhibitor. Ion exchange chromatography of cytosol derived from TNF-treated EC consistently showed an ~ 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-α 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 IV 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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Cell Physiology
Volume268
Issue number5 37-5
StatePublished - Jan 1 1995
Externally publishedYes

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Endothelial Cells
Tumor Necrosis Factor-alpha
Cyclic Nucleotides
Phosphoric Diester Hydrolases
Type 4 Cyclic Nucleotide Phosphodiesterase
spleen exonuclease
Monokines
Rolipram
Phenotype
Thrombomodulin
1-Methyl-3-isobutylxanthine
Messenger RNA
Phosphodiesterase Inhibitors
Inulin
Sorbitol
Ion Exchange Chromatography
Capillary Permeability
Post Translational Protein Processing
Cyclic AMP
Cytosol

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cell Biology

Cite this

Koga, S., Morris, S., Ogawa, S., Liao, H., Bilezikian, J. P., Chen, G., ... Pinsky, D. J. (1995). TNF modulates endothelial properties by decreasing cAMP. American Journal of Physiology - Cell Physiology, 268(5 37-5).

TNF modulates endothelial properties by decreasing cAMP. / Koga, S.; Morris, S.; Ogawa, S.; Liao, H.; Bilezikian, J. P.; Chen, G.; Thompson, W. J.; Ashikaga, T.; Brett, J.; Stern, David; Pinsky, D. J.

In: American Journal of Physiology - Cell Physiology, Vol. 268, No. 5 37-5, 01.01.1995.

Research output: Contribution to journalArticle

Koga, S, Morris, S, Ogawa, S, Liao, H, Bilezikian, JP, Chen, G, Thompson, WJ, Ashikaga, T, Brett, J, Stern, D & Pinsky, DJ 1995, 'TNF modulates endothelial properties by decreasing cAMP', American Journal of Physiology - Cell Physiology, vol. 268, no. 5 37-5.
Koga S, Morris S, Ogawa S, Liao H, Bilezikian JP, Chen G et al. TNF modulates endothelial properties by decreasing cAMP. American Journal of Physiology - Cell Physiology. 1995 Jan 1;268(5 37-5).
Koga, S. ; Morris, S. ; Ogawa, S. ; Liao, H. ; Bilezikian, J. P. ; Chen, G. ; Thompson, W. J. ; Ashikaga, T. ; Brett, J. ; Stern, David ; Pinsky, D. J. / TNF modulates endothelial properties by decreasing cAMP. In: American Journal of Physiology - Cell Physiology. 1995 ; Vol. 268, No. 5 37-5.
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abstract = "Tumor necrosis factor-α (TNF-α), 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 [ 3 H]sorbitol, [ 3 H]inulin, and 125 I-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-α showed increased cAMP levels when exposed to 3- isobutyl-1-methylxanthine, a nonspecific CNPDE inhibitor. Ion exchange chromatography of cytosol derived from TNF-treated EC consistently showed an ~ 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-α 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 IV 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.",
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AU - Liao, H.

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AU - Chen, G.

AU - Thompson, W. J.

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AU - Brett, J.

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