In the CNS, astrocytes are significant sources of RANTES/CCL5 (regulated upon 
activation, normal T cell expressed and secreted), a CC-chemokine with important 
biological function. Astrocyte RANTES/CCL5 has been shown to be induced by 
interleukin-1 (IL-1), with interferon-gamma (IFNgamma) as a primer, but whether 
type I interferons play any role in the expression of RANTES/CCL5 is not known. 
In this report, we studied the detailed mechanism of RANTES/CCL5 induction in 
primary human astrocytes activated with IL-1 and IFNbeta. Ribonuclease 
protection assay and ELISA showed that IFNbeta, although not effective alone, 
increased IL-1-induced RANTES/CCL5 expression, but did not antagonize IFNgamma. 
IL-1 or IL-1/IFNbeta-induced RANTES/CCL5 expression was inhibited by the 
super-repressor IkappaBalpha or inhibitors of p38 or c-Jun N-terminal kinase 
(JNK) MAPKs (mitogen-activated protein kinases), but not by extracellular signal 
regulated kinases (ERK) inhibitors. IFNbeta enhanced IL-1-induced 
phosphorylation of p38 MAPK, but was not effective alone. Transfection with 
mutated RANTES/CCL5 promoter-reporter constructs revealed that kappaB, 
interferon-stimulated response element (ISRE) and CAATT-enhancer binding 
protein-beta (C/EBPbeta) sites all contributed to IL-1/IFNbeta-induced 
RANTES/CCL5 transcription. IFNbeta synergized with IL-1 to induce nuclear 
accumulation of C/EBPbeta protein. They also synergized to form nuclear ISRE 
complexes with Stat1, Stat2 and interferon regulatory factor-1 (IRF-1) proteins. 
Together, our results demonstrate that IFNbeta plays a positive regulatory role 
in the expression of RANTES/CCL5 in human astrocytes through several distinct 
mechanisms.