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Molecular and Cellular Biology, July 2003, p. 4841-4858, Vol. 23, No. 14
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.14.4841-4858.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

C/EBPß Regulation in Lipopolysaccharide-Stimulated Macrophages

Michelle N. Bradley, Liang Zhou, and Stephen T. Smale*

Howard Hughes Medical Institute and Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California 90095-1662

Received 19 February 2003/ Returned for modification 10 April 2003/ Accepted 22 April 2003

C/EBP family members contribute to the induction of the interleukin-12 p40 gene and the genes encoding several other mediators of inflammation. Here, we show by chromatin immunoprecipitation that C/EBPß binds the p40 promoter following lipopolysaccharide stimulation of peritoneal macrophages. However, three modes of C/EBPß regulation reported in other cell types were not detected, including alternative translation initiation, nuclear translocation, and increased DNA binding following posttranslational modification. In contrast, C/EBPß concentrations greatly increased following stimulation via MAP kinase-dependent induction of C/EBPß gene transcription. Increased C/EBPß concentrations were unimportant for p40 induction, however, as transcription of the p40 gene initiated before C/EBPß concentrations increased. Furthermore, disruption of C/EBPß upregulation by a MAP kinase inhibitor only slightly diminished p40 induction. Phosphopeptide mapping revealed that endogenous C/EBPß in macrophages is phosphorylated on only a single tryptic peptide containing 14 potential phosphoacceptors. This peptide was constitutively phosphorylated in primary and transformed macrophages, in contrast to its inducible phosphorylation in other cell types in response to Ras and growth hormone signaling. Altered-specificity experiments supported the hypothesis that C/EBPß activity in macrophages does not require an inducible posttranslational modification. These findings suggest that, although C/EBPß contributes to the induction of numerous proinflammatory genes, it is fully active in unstimulated macrophages and poised to stimulate transcription in conjunction with other factors whose activities are induced.

* Corresponding author. Mailing address: Howard Hughes Medical Institute, UCLA, 6-730, MRL, 675 Charles E. Young South, Los Angeles, CA 90095-1662. Phone: (310) 206-4777. Fax: (310) 206-8623. E-mail: smale{at}mednet.ucla.edu.

Molecular and Cellular Biology, July 2003, p. 4841-4858, Vol. 23, No. 14
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.14.4841-4858.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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