Evidence for a GTP-binding protein involved in interferon-gamma transduction signal.
These studies were designed to investigate the characteristics of the intracellular messengers induced by interferons (IFN-alpha/beta and IFN-gamma) after receptor binding. Pretreatment of target cells with V. cholerae toxin, which is known to activate a membrane GTP-binding stimulatory protein (Gs), potentiated the action of IFN-gamma, but not of IFN-alpha/beta. By contrast, B. pertussis toxin, which is known to activate the GTP-binding inhibitory protein (Gi), had no effects on the action of both IFN-alpha/beta and IFN-gamma. Further support to the involvement of G proteins in IFN-gamma transduction signal came from the finding that a non-hydrolizable GTP analog, GTP-gamma-S, enhanced in the presence of phorbol esters (PMA) the antiviral and antiproliferative activity of IFN-gamma, but not of IFN-alpha/beta. On the other hand, forskolin or PGE1, known to increase the intracellular cAMP levels by different metabolic pathways, when added together with IFN-gamma, significantly potentiated its antiviral and antiproliferative activity. Pretreatment of the cultures with the above drugs completely prevented IFN-gamma activity. No effects were observed when forskolin or PGE1 were used with IFN-alpha/beta. Finally, the modulation of IFN-gamma activity by the above drugs was not a consequence of changes in the expression of the specific surface receptors, since [125I]IFN-gamma binding by pretreated target cells was comparable to that of untreated cultures. Altogether these results demonstrate that the IFN-gamma, but not the IFN-alpha/beta, transduction signal is mediated after receptor binding by a G protein with functional characteristics similar to those of the known Gs proteins. Activation of the adenylate cyclase system could be one of the subsequent steps involved in IFN-gamma action.
D037361:Adenylate Cyclase Toxin; D000527:Alprostadil / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D002772:Cholera Toxin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000502:physiology*; D007371:Interferon-gamma / Q000494:pharmacology*; D051379:Mice; D010539:Permeability; D037342:Pertussis Toxin; D011994:Recombinant Proteins; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D011994:Recombinant Proteins; D010566:Virulence Factors, Bordetella; D005576:Colforsin; D007371:Interferon-gamma; D002772:Cholera Toxin; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D000527:Alprostadil