Biphasic effect of cAMP-elevating agents on ICAM-1 expression stimulated by retinoic acid and interferon gamma.
Incubation of the human glioma cell line HS 683 in the presence of IFN-gamma or retinoic acid strongly stimulates the cell-surface expression of the intercellular adhesion molecule ICAM-1. We have investigated the role of the cAMP-mediated signal transduction pathway in this process and report that pharmacological agents which increased the intracellular levels of cAMP exhibited a biphasic action on ICAM-1 expression in human glioma cell line HS 683. Treatment for 1 hr with 25 microM forskolin or 1 mM isobutylmethylxanthine, or for 12 hr with 100 ng/ml pertussis toxin or 50 micrograms/ml cholera toxin transiently stimulated ICAM-1 expression with a maximal level of expression 8 hr post treatment, after which time ICAM-1 expression returned to the basal level. On the other hand, such pretreatments inhibited the inducing effects of either retinoic acid or IFN-gamma. Indeed, 24 hr after treatment with cAMP-elevating agents, both the retinoic-acid- and the IFN-gamma-induced ICAM-1 expression were inhibited by 60 to 80%, with a maximal 90 to 100% inhibition 72 hr post treatment. This inhibition of the cell-surface expression of ICAM-1 was confirmed at the mRNA level. The intracytoplasmic levels of cAMP were also quantified following treatments with forskolin, retinoic acid or IFN-gamma. In response to forskolin, cAMP levels increased 30-fold within 5 min, whereas a 10-fold increase occurred 60 min following treatment with 10 microM retinoic acid. Interferon gamma, in contrast, did not induce cAMP accumulation. These results were also correlated with an in vitro activation of adenylyl cyclase activity by retinoic acid and inhibition of this activity by IFN-gamma, in a dose-dependent and a GTP-dependent manner. Our results suggest that the suppression of IFN-gamma-induced ICAM-1 expression, obtained upon pre-treatment with cAMP-elevating agents, is due to direct antagonism with IFN-gamma action on adenylyl cyclase. However, the inhibition of retinoic-acid-induced ICAM-1 expression cannot be explained by the same mechanisms. The timing of adenylyl cyclase stimulation and cAMP accumulation, as well as the levels of cAMP accumulation, are probably involved in this inhibition. Our results also emphasize the fact that the induction of ICAM-1 expression is a multi-step process implicating different transductional signals among which cAMP might be involved as a second messenger.
Molecular Endocrinology Unit, CHUL Research Center, Laval University, Ste-Foy, Quebec, Canada.
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Bouillon
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Fortier
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Boulianne
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D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000187:drug effects / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics*; D002772:Cholera Toxin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000502:physiology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007700:Kinetics; D037342:Pertussis Toxin; D011994:Recombinant Proteins; D013268:Stimulation, Chemical; D013997:Time Factors; D014212:Tretinoin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D015815:Cell Adhesion Molecules; D011994:Recombinant Proteins; D010566:Virulence Factors, Bordetella; D018799:Intercellular Adhesion Molecule-1; D005576:Colforsin; D014212:Tretinoin; D007371:Interferon-gamma; D006160:Guanosine Triphosphate; D002772:Cholera Toxin; D000242:Cyclic AMP; D037342:Pertussis Toxin; D000262:Adenylyl Cyclases; D015056:1-Methyl-3-isobutylxanthine