RETRACTED: FUNCTIONAL NF-IL6/CCAAT ENHANCER-BINDING PROTEIN IS REQUIRED FOR TUMOR-NECROSIS-FACTOR ALPHA-INDUCIBLE EXPRESSION OF THE GRANULOCYTE-COLONY-STIMULATING FACTOR (CSF), BUT NOT THE GRANULOCYTE-MACROPHAGE CSF OR INTERLEUKIN-6 GENE IN HUMAN FIBROBLASTS (RETRACTED ARTICLE. SEE VOL 186, PG 171, 1997)

被引:25
作者
KIEHNTOPF, M
HERRMANN, F
BRACH, MA
机构
[1] FREE UNIV BERLIN, KLINIKUM RUDOLF VIRCHOW, ROBERT ROSSLE CANC CTR, DEPT MED ONCOL & APPL MOLEC BIOL, D-13122 BERLIN, GERMANY
[2] MAX DELBRUCK CTR MOLEC MED, D-13122 BERLIN, GERMANY
关键词
D O I
10.1084/jem.181.2.793
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Tumor necrosis factor (TNF) alpha participates in the regulation of the acute-phase, immune, and inflammatory responses. Target genes known to be transcriptionally activated by TNF-alpha include the granulocyte (G)-colony-stimulating factor (CSF) gene, the granulocyte/macrophage (GM)-CSF gene, as well as the interleukin (IL) 6 gene. Functional nuclear factor (NF)-IL6 recognition sites have been identified in regulatory regions of these genes by transient transfection studies using deleted promoter constructs. In addition, NF-IL6 is known to form heterodimeric complexes with the NF-kappa B transcription factor, which is also engaged in the transcriptional regulation of these genes. The indispensable importance of NF-IL6 for regulating gene expression of proinflammatory cytokine genes in response to inflammatory stimuli in vivo remains, however, unclear. We here report, by using both antisense (AS) oligodesoxyribonucleotide (ODN) and ribozyme (RZ)-mediated specific elimination of NF-IL6 transcripts in human fibroblasts, that TNF-alpha-induced synthesis of G-CSF, but not of GM-CSF or IL-6, is abolished in the absence of functional NF-IL6 in vivo. Both AS ODN and RZ targeting of the NF-IL6 transcript eliminate NF-IL6 protein, as shown in Western blot analysis and electrophoretic mobility shift assays. Similarly, fibroblasts exposed to either the AS NF-IL6 ODN or the NF-IL6 RZ, but not to the sense or nonsense ODN or a mutated ribozyme, also failed to respond with functional activation of NF-IL6 as assayed in transient transfection studies using heterologous promoter constructs harboring the NF-IL6 recognition site. In contrast, protein synthesis, DNA-binding activity, and transcriptional activation capacity of the NF-kappa B transcription factor is not impaired upon exposure to either ODN or RZ. Fibroblasts that had been cultured in the presence of the AS NF-IL6 ODN or the NF-IL6RZ failed to synthesize G-CSF protein in response to TNF-alpha, while TNF-alpha-inducible transcription and release of GM-CSF and IL-6 was preserved.
引用
收藏
页码:793 / 798
页数:6
相关论文
共 24 条
[1]   A NUCLEAR FACTOR FOR IL-6 EXPRESSION (NF-IL6) IS A MEMBER OF A C/EBP FAMILY [J].
AKIRA, S ;
ISSHIKI, H ;
SUGITA, T ;
TANABE, O ;
KINOSHITA, S ;
NISHIO, Y ;
NAKAJIMA, T ;
HIRANO, T ;
KISHIMOTO, T .
EMBO JOURNAL, 1990, 9 (06) :1897-1906
[2]   IL-6 AND NF-IL6 IN ACUTE-PHASE RESPONSE AND VIRAL-INFECTION [J].
AKIRA, S ;
KISHIMOTO, T .
IMMUNOLOGICAL REVIEWS, 1992, 127 :25-50
[3]  
ARAI K, 1990, ANNU REV BIOCHEM, V59, P783, DOI 10.1146/annurev.bi.59.070190.004031
[4]  
BAEUERLE PA, 1994, ANNU REV IMMUNOL, V12, P141, DOI 10.1146/annurev.immunol.12.1.141
[5]   THE MITOGENIC RESPONSE TO TUMOR-NECROSIS-FACTOR ALPHA-REQUIRES C-JUN/AP-1 [J].
BRACH, MA ;
GRUSS, HJ ;
SOTT, C ;
HERRMANN, F .
MOLECULAR AND CELLULAR BIOLOGY, 1993, 13 (07) :4284-4290
[6]  
BRACH MA, 1993, J BIOL CHEM, V268, P8466
[7]   REQUIREMENT FOR NUCLEAR FACTOR (NF)-KAPPA-B P65 AND NF-INTERLEUKIN-6 BINDING-ELEMENTS IN THE TUMOR-NECROSIS-FACTOR RESPONSE REGION OF THE GRANULOCYTE-COLONY-STIMULATING FACTOR PROMOTER [J].
DUNN, SM ;
COLES, LS ;
LANG, RK ;
GERONDAKIS, S ;
VADAS, MA ;
SHANNON, MF .
BLOOD, 1994, 83 (09) :2469-2479
[8]  
GRUSS HJ, 1992, BLOOD, V80, P2563
[9]  
HIMES SR, 1993, ONCOGENE, V8, P3189
[10]   CONSTITUTIVE AND INTERLEUKIN-1 (IL-1)-INDUCIBLE FACTORS INTERACT WITH THE IL-1-RESPONSIVE ELEMENT IN THE IL-6 GENE [J].
ISSHIKI, H ;
AKIRA, S ;
TANABE, O ;
NAKAJIMA, T ;
SHIMAMOTO, T ;
HIRANO, T ;
KISHIMOTO, T .
MOLECULAR AND CELLULAR BIOLOGY, 1990, 10 (06) :2757-2764