ABSTRACT
C/EBPalpha, beta, and delta are all expressed by bone marrow-derived macrophages. Ectopic expression of any of these transcription factors is sufficient to confer lipopolysaccharide (LPS)-inducible expression of interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) to a B lymphoblast cell line, which normally lacks C/EBP factors and does not display LPS induction of proinflammatory cytokines. Thus, the activities of C/EBPalpha, beta, and delta are redundant in regard to expression of IL-6 and MCP-1. Surprisingly, the bZIP region of C/EBPbeta, which lacks any previously described activation domains, can also confer LPS-inducible expression of IL-6 and MCP-1 in stable transfectants. Transient transfections reveal that the bZIP regions of C/EBPbeta, C/EBPdelta, and, to a lesser extent, C/EBPalpha can activate the IL-6 promoter and augment its induction by LPS. Furthermore, the transdominant inhibitor, LIP, can activate expression from the IL-6 promoter. The ability of the C/EBPbeta bZIP region to activate the IL-6 promoter in transient transfections is completely dependent upon an intact NF-kappaB-binding site, supporting a model where the bZIP protein primarily functions to augment the activity of NF-kappaB. Replacement of the leucine zipper of C/EBPbeta with that of GCN4 yields a chimeric protein that can dimerize and specifically bind to a C/EBP consensus sequence, but shows a markedly reduced ability to activate IL-6 and MCP-1 expression. These results implicate the leucine zipper domain in some function other than dimerization with known C/EBP family members, and suggest that C/EBP redundancy in regulating cytokine expression may result from their highly related bZIP regions.
Subject(s)
Chemokine CCL2/biosynthesis , DNA-Binding Proteins/metabolism , Interleukin-6/biosynthesis , Leucine Zippers/genetics , Lipopolysaccharides/pharmacology , Nuclear Proteins/metabolism , Saccharomyces cerevisiae Proteins , Transcription Factors/metabolism , Animals , B-Lymphocytes , Binding Sites , CCAAT-Enhancer-Binding Protein-beta , CCAAT-Enhancer-Binding Proteins , Cell Line , Chemokine CCL2/genetics , DNA-Binding Proteins/genetics , Dimerization , Fungal Proteins/genetics , Gene Expression Regulation , Interleukin-6/genetics , Mice , NF-kappa B/metabolism , Nuclear Proteins/analysis , Nuclear Proteins/genetics , Promoter Regions, Genetic , Protein Isoforms/metabolism , Protein Kinases/genetics , Recombinant Fusion Proteins/genetics , Repressor Proteins/pharmacology , Transcription Factors/genetics , Transcriptional Activation , TransfectionABSTRACT
To complement existing institution-based drug use surveys, a street intercept survey of 581 young illicit drug users was conducted in Sydney, Australia. Patterns of use, reasons for use and awareness of the health risks associated with use were investigated. The most commonly used illicit drug type, after marijuana, was amphetamines. The least popular illicit drug was heroin. Most of the sample used occasionally, exhibiting a controlled pattern of use with a low prevalence of problems associated with use. Heroin users, in contrast, were often frequent users and reported a higher prevalence of associated problems. The majority of the sample reported excessive drinking patterns, indicating that the current policy of emphasis on alcohol misuse rather than illicit drug use amongst youth is appropriate.
