Cyclic AMP potentiation of cytokine-induced nitric oxide synthase activity in a murine astrocyte cell line.
Astrocytes in culture have been previously shown to express inducible nitric oxide synthase (iNOS) following treatment with cytokines such as interleukin-1 beta (IL-1 beta) and interferon-gamma (IFN-gamma). We report here on the effects of the cyclic nucleotide analogues 8-bromo-cyclic AMP and 8-bromo-cyclic GMP on cytokine-stimulated iNOS gene expression in a cultured murine astrocyte cell line. In these cells, neither 8-bromo-cyclic AMP nor 8-bromo-cyclic GMP alone was able to stimulate iNOS activity. Similarly, neither IL-1 beta nor IFN-gamma was capable of independently stimulating iNOS expression. Co-stimulation with both cytokines, however, resulted in measurable increases in iNOS activity, and correlated to increases in iNOS mRNA levels. The addition of 8-bromo-cyclic AMP, but not 8-bromo-cyclic GMP, was found to further enhance the expression of iNOS activity induced by IL-1 beta and IFN-gamma co-stimulation. This potentiation effect of 8-bromo-cyclic AMP correlated to a further elevation in iNOS mRNA levels over that produced by cytokine co-stimulation alone. However, 8-bromo-cyclic AMP co-treatment with either cytokine alone did not stimulate iNOS activity, indicating that the signal transduction pathway(s) involved in the potentiation effect of 8-bromo-cyclic AMP is functional only in the presence of both cytokines. These results indicate that cyclic AMP-mediated processes can participate in modulating the expression of astrocyte iNOS when the appropriate combinations of stimulatory cytokines are present.
Burgher
K L
KL
Hoechst Marion Roussel Inc., Bridgewater, NJ 08807, USA.
Heroux
J A
JA
Ringheim
G E
GE
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000201:enzymology*; D002460:Cell Line; D000242:Cyclic AMP / Q000494:pharmacology*; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D004790:Enzyme Induction; D007371:Interferon-gamma / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology*; D051379:Mice; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*
D007375:Interleukin-1; D015124:8-Bromo Cyclic Adenosine Monophosphate; C016276:8-bromocyclic GMP; D007371:Interferon-gamma; D000242:Cyclic AMP; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP