Cooperative interaction of nuclear factor-kappa B- and cis-regulatory enhancer binding protein-like factor binding elements in activating the interleukin-8 gene by pro-inflammatory cytokines.
A novel cytokine, interleukin-8 (IL-8), may play major roles in the inflammatory process by recruiting neutrophils and T cells into inflammatory sites. The production of this cytokine is not constitutive and is induced in a variety of cell types by stimulation with mitogens and cytokines. Among cytokines, only IL-1 and tumor necrosis factor (TNF) can induce IL-8 gene expression at the transcriptional level. Transfection of a human fibrosarcoma cell line with chloramphenicol acetyltransferase expression plasmids linked to a 5'-flanking deletion mutants of the IL-8 gene demonstrated that the nucleotides between -94 and -71 base pairs from the start of the first exon are essential and sufficient for the IL-8 induction by either IL-1, TNF, or phorbol 12-myristate 13-acetate. This sequence is composed of two cis-elements; one is the potential binding site for a nuclear factor-kappa B-like factor and the other for a cis-regulatory enhancer binding protein-like factor. Mutations in either elements abolished IL-1, TNF, and phorbol 12-myristate 13-acetate responsiveness. This report provides the first evidence that cooperation between two distinct cis-elements may be required for induction of gene expression by either IL-1 or TNF.
Mukaida
N
N
Biological Response Modifiers Program, National Cancer Institute-Frederick Cancer Research and Development Center, Maryland 21702-1201.
Mahe
Y
Y
Matsushima
K
K
D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D005091:Exons; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation; D007375:Interleukin-1 / Q000494:pharmacology; D016209:Interleukin-8 / Q000235:genetics*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D015345:Oligonucleotide Probes; D011994:Recombinant Proteins / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D022762:CCAAT-Enhancer-Binding Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D007375:Interleukin-1; D016209:Interleukin-8; D016328:NF-kappa B; D009687:Nuclear Proteins; D015345:Oligonucleotide Probes; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D013755:Tetradecanoylphorbol Acetate