INHIBITION OF LIPOPOLYSACCHARIDE-INDUCED IL-1-BETA TRANSCRIPTION BY CYCLIC ADENOSINE-MONOPHOSPHATE IN HUMAN ASTROCYTIC CELLS

The response to LPS includes synthesis by monocytes of the inflammator y mediator IL-1 beta. Although the intracellular signaling pathways ac tivated by LPS that lead to IL-1 beta production have been studied ext ensively in monocytes, these pathways have not been investigated in as trocytes, an important source of IL-1 beta in the central nervous syst em. cAMP has been implicated in LPS signaling as a positive regulator of IL-1 beta mRNA accumulation in monocytes. In this study, we demonst rate that in human astrocytes (both fetal and the astrocytoma cell lin e, U-373 MG), agents that elevate intracellular cAMP decrease LPS-indu ced IL-1 beta mRNA accumulation. Elevated intracellular cAMP does not affect IL-1 beta mRNA stability, but inhibits LPS-induced transcriptio n initiation of IL-1 beta in U-373 MG cells. Elevated intracellular cA MP may be a negative feedback regulatory mechanism to inhibit IL-1 bet a production employed by astrocytes that (unlike monocytic cells) lack a glycosyl-phosphatidylinositol (GPI)-anchored form of the LPS recept or, CD14. Whether cAMP inhibits an LPS-inducible signaling pathway or negatively affects cAMP-dependent transcription factors remains to be determined.