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Mol Cell Biol, May 1998, p. 2815-2824, Vol. 18, No. 5
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Tumor Necrosis Factor Alpha Gene Regulation: Enhancement of C/EBPbeta -Induced Activation by c-Jun

Alexander Zagariya,1 Shubhangee Mungre,1 Rosa Lovis,1 Michael Birrer,2 Scott Ness,3 Bayar Thimmapaya,4 and Richard Pope1,*

Department of Medicine, Division of Arthritis, and Veterans Administration Lakeside Medical Center,1 and Department of Microbiology and Immunology,4 Northwestern University Medical School, Chicago, Illinois 60611; Department of Cell and Cancer Biology, National Cancer Institute, National Institutes of Health, Rockville, Maryland 208052; and Department of Biochemistry, Molecular Biology and Cell Biology, Northwestern University, Evanston, Illinois 60208-35003

Received 5 November 1997/Returned for modification 8 January 1998/Accepted 12 February 1998

Tumor necrosis factor alpha (TNFalpha ) is a key regulatory cytokine whose expression is controlled by a complex set of stimuli in a variety of cell types. Previously, we found that the monocyte/macrophage-enriched nuclear transcription factor C/EBPbeta played an important role in the regulation of the TNFalpha gene in myelomonocytic cells. Abundant evidence suggests that other transcription factors participate as well. Here we have analyzed interactions between C/EBPbeta and c-Jun, a component of the ubiquitously expressed AP-1 complex. In phorbol myristate acetate (PMA)-treated Jurkat T cells, which did not possess endogenous C/EBPbeta , expression of c-Jun by itself had relatively little effect on TNFalpha promoter activity. However, the combination of C/EBPbeta and c-Jun was synergistic, resulting in greater than 130-fold activation. This effect required both the leucine zipper and DNA binding domains, but not the transactivation domain, of c-Jun, plus the AP-1 binding site centered 102/103 bp upstream of the transcription start site in the TNFalpha promoter. To determine if C/EBPbeta and c-Jun might cooperate to regulate the cellular TNFalpha gene in myelomonocytic cells, U937 cells that possess endogenous C/EBPbeta and were stably transfected with either wild-type c-Jun or the transactivation domain deletion mutant (TAM-67) were examined. U937 cells expressing ectopic wild-type c-Jun or TAM-67 secreted over threefold more TNFalpha than the control line in response to PMA plus lipopolysaccharide. Transient transfection of the U937 cells expressing TAM-67 suggested that TAM-67 binding to the -106/-99-bp AP-1 binding site cooperated with endogenous C/EBPbeta in the activation of the -120 TNFalpha promoter-reporter. DNA binding assays using oligonucleotides derived from the TNFalpha promoter suggested that C/EBPbeta and c-Jun interact in vitro and that the interaction may be DNA dependent. Our data demonstrate that the TNFalpha gene is regulated by the interaction of the ubiquitous AP-1 complex protein c-Jun and the monocyte/macrophage-enriched transcription factor C/EBPbeta and that this interaction contributes to the expression of the cellular TNFalpha gene in myelomonocytic cells. This interaction was unique in that it did not require the c-Jun transactivation domain, providing new insight into the cell-type-specific regulation of the TNFalpha gene.

* Corresponding author. Mailing address: Department of Medicine, Division of Arthritis, Northwestern University Medical School, Ward 3-315, 303 E. Chicago Ave., Chicago, IL 60611. Phone: (312) 503-8197. Fax: (312) 503-0994. E-mail: rmp158{at}nwu.edu.

Mol Cell Biol, May 1998, p. 2815-2824, Vol. 18, No. 5
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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