Elevation of cyclic AMP levels in astrocytes antagonizes cytokine-induced adhesion molecule expression.
We have examined the effect of elevating cyclic AMP levels on cytokine-mediated enhancement of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) gene expression by astrocytes. Treatment of astrocytes with the cyclic AMP mimetic dibutyryl-cyclic AMP, or the agonists norepinephrine, forskolin, prostaglandin E2, and cholera toxin alone had no effect on ICAM-1 or VCAM-1 mRNA gene expression. However, elevating cyclic AMP levels within the cells by these agents suppressed interleukin-1beta- and tumor necrosis factor-alpha-induced adhesion molecule expression at both the mRNA and protein levels. The phosphodiesterase type IV inhibitor, rolipram, was able to potentiate the inhibitory effect of forskolin on ICAM-1 and VCAM-1 gene expression. Inhibition of tumor necrosis factor-alpha-induced VCAM-1 mRNA levels by forskolin was partially due to enhanced degradation of VCAM-1 message, whereas the decay rates of tumor necrosis factor-alpha-induced ICAM-1 message and interleukin-1beta-induced ICAM-1/VCAM-1 message were not affected by forskolin treatment. These results demonstrate that the pathways used by interleukin-1beta and tumor necrosis factor-alpha to induce adhesion molecule expression are antagonized by cyclic AMP-dependent protein kinase-mediated signaling pathways.
Ballestas
M E
ME
Department of Cell Biology, University of Alabama at Birmingham, 35294-0005, U.S.A.
Benveniste
E N
EN
D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D016207:Cytokines / Q000494:pharmacology*; D004355:Drug Stability; D004357:Drug Synergism; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D020889:Rolipram; D013268:Stimulation, Chemical; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D015815:Cell Adhesion Molecules; D016207:Cytokines; D007375:Interleukin-1; D011760:Pyrrolidinones; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D005576:Colforsin; D000242:Cyclic AMP; D020889:Rolipram