Granulocyte-macrophage colony-stimulating factor and interleukin-4 differentially regulate the human tumor necrosis factor-alpha promoter region.
Regulation of TNF-alpha promoter activity by IL-2, IFN-gamma, GM-CSF, and IL-4 was examined in the U937 macrophage cell line and the MLA 144 T cell line. Using a transient transfection system, the full-length TNF-alpha promoter was examined for response to these cytokine signals. Only GM-CSF was able to consistently induce a twofold activation of the TNF-alpha promoter in the U937 cell line. GM-CSF activation of the promoter region was further analyzed using a series of 5' truncations and site mutations of the AP-1, AP-2, and CRE sites of the promoter. The GM-CSF activation mapped to the region contained within the 95 base pairs upstream from the transcription start site (TSS) with the AP-2 site as a putative cis-acting sequence. IL-4 profoundly inhibited both basal and phorbol ester-induced TNF-alpha promoter activity as well as protein production. Promoter inhibition by IL-4 required the 95-bp basal promoter sequence.
Rhoades
K L
KL
Department of Microbiology and Immunology, UCLA School of Medicine 90024.
Cai
S
S
Golub
S H
SH
Economou
J S
JS
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D004252:DNA Mutational Analysis; D005786:Gene Expression Regulation / Q000187:drug effects*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D006922:Hylobates; D015847:Interleukin-4 / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics*; D013601:T-Lymphocytes / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D013755:Tetradecanoylphorbol Acetate