期刊
JOURNAL OF NEUROCHEMISTRY
卷 90, 期 2, 页码 297-308出版社
WILEY
DOI: 10.1111/j.1471-4159.2004.02487.x
关键词
brain; chemokine; human; promoter; transcription
资金
- NIAID NIH HHS [AI44641] Funding Source: Medline
- NIMH NIH HHS [MH55477] Funding Source: Medline
- NINDS NIH HHS [NS11920] Funding Source: Medline
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.
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