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 inflammatory mediator IL-1 beta. Although the intracellular signaling pathways activated by LPS that lead to IL-1 beta production have been studied extensively in monocytes, these pathways have not been investigated in astrocytes, an important source of IL-1 beta in the central nervous system. cAMP has been implicated in LPS signaling as a positive regulator of IL-1 beta mRNA accumulation in monocytes. In this study, we demonstrate that in human astrocytes (both fetal and the astrocytoma cell line, U-373 MG), agents that elevate intracellular cAMP decrease LPS-induced IL-1 beta mRNA accumulation. Elevated intracellular cAMP does not affect IL-1 beta mRNA stability, but inhibits LPS-induced transcription initiation of IL-1 beta in U-373 MG cells. Elevated intracellular cAMP may be a negative feedback regulatory mechanism to inhibit IL-1 beta production employed by astrocytes that (unlike monocytic cells) lack a glycosyl-phosphatidylinositol (GPI)-anchored form of the LPS receptor, CD14. Whether cAMP inhibits an LPS-inducible signaling pathway or negatively affects cAMP-dependent transcription factors remains to be determined.