Regulation of RANTES/CCL5 expression in human astrocytes by interleukin-1 and interferon-beta.
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.
Kim
Mee-Ohk
MO
Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Suh
Hyeon-Sook
HS
Brosnan
Celia F
CF
Lee
Sunhee C
SC
D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000235:genetics* / Q000378:metabolism; D019742:Chemokines, CC / Q000235:genetics* / Q000378:metabolism; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D017930:Genes, Reporter; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology / Q000502:physiology*; D007375:Interleukin-1 / Q000494:pharmacology / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020218:Response Elements / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
D022782:CCAAT-Enhancer-Binding Protein-beta; C483024:CCL5 protein, human; D018946:Chemokine CCL5; D019742:Chemokines, CC; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D016328:NF-kappa B; D012333:RNA, Messenger; D016899:Interferon-beta; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases