cAMP differentially regulates expression of mRNA encoding IL-1 alpha and IL-1 beta in murine peritoneal macrophages.
The influence of PGE2 and the consequent rise in intracellular cAMP on LPS-induced IL-1 alpha and IL-1 beta mRNA levels has been examined in murine peritoneal macrophages. As has been previously reported, neither PGE2 nor dibutyryl cAMP modulated the levels of LPS-induced IL-1 alpha mRNA. In contrast, the levels of IL-1 beta mRNA were markedly potentiated (greater than 10 fold) under the same experimental conditions. This effect was due to elevation of intracellular cAMP because other agents known to elevate cAMP levels (e.g., cholera toxin, forskolin, 1-isomethyl-3-isobutylxanthine) had the same selective effect on IL-1 beta mRNA levels. PGE2 and dBcAMP not only potentiated LPS-induced IL-1 beta mRNA levels but were also able to stimulate modest accumulation of IL-1 beta mRNA in the absence of LPS. Although measurement of IL-1 activity by bioassay suggested that dBcAMP and PGE2 could suppress LPS-induced IL-1 expression, levels of IL-1 protein, determined by radioreceptor assay, were markedly elevated. cAMP did not appreciably alter the stability of either IL-1 alpha or IL-1 beta mRNA. Instead dBcAMP independently stimulated the transcriptional activity of the IL-1 beta gene. In concert the results demonstrate that cAMP can modulate the response of mononuclear phagocytes to LPS in a complex pattern; gene expression may be unaltered, suppressed, or potentiated and will thereby affect both the quality and magnitude of the ensuing inflammatory response.
Ohmori
Y
Y
Research Institute, Cleveland Clinic Foundation, OH 44195-5069.
Strassman
G
G
Hamilton
T A
TA
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D000242:Cyclic AMP / Q000032:analysis / Q000502:physiology*; D015232:Dinoprostone / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D010529:Peritoneal Cavity / Q000166:cytology; D012333:RNA, Messenger / Q000032:analysis*; D014158:Transcription, Genetic / Q000187:drug effects
D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D003994:Bucladesine; D000242:Cyclic AMP; D015232:Dinoprostone