Regulation of interleukin-8 gene expression.
Interleukin-8 (IL-8), a member of the CXC chemokine family, is an important activator and chemoattractant for neutrophils and has been implicated in a variety of inflammatory diseases. IL-8 is secreted in a stimulus-specific manner by a wide variety of cell types and is regulated primarily at the level of gene transcription. Functional studies indicate that IL-8 transcriptional responses to proinflammatory mediators are rapid and require only 100 nucleotides of 5'-flanking DNA upstream of the TATA box. Within the IL-8 promoter sequence are DNA binding sites for the inducible transcription factors AP-1, NF-IL-6, and NF-kappaB. Transcription factors in these families bind the IL-8 promoter as dimers, and several distinct subunit combinations have been identified as important for IL-8 transcription. In addition, these factors can act in concert to synergistically activate the IL-8 promoter. AP-1 and NF-IL-6 physically interact with NF-kappaB, and functional cooperativity among the factors appears to be critical for optimal IL-8 promoter activity in different cell types. IL-8 transcription appears to be activated by a promoter recruitment mechanism where inducible transcription factor binding to the IL-8 promoter is required for binding of constitutively active TATA box-binding proteins and formation of a stable preinitiation complex. This review discusses the regulatory role these higher-order synergistic interactions play in IL-8 transcription and in generation of the stimulus-specific and cell type-specific patterns of IL-8 expression.
Roebuck
K A
KA
Department of Immunology/Microbiology, Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL 60612, USA. kroebuck@rush.edu
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000502:physiology; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000378:metabolism
D016209:Interleukin-8; D016328:NF-kappa B; D014157:Transcription Factors