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This Article Full Text Full Text (PDF) All Versions of this Article: 288/1/F117    most recent 00333.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Pan, L. Articles by Gross, K. W. Search for Related Content PubMed PubMed Citation Articles by Pan, L. Articles by Gross, K. W.

Enhancer-dependent inhibition of mouse renin transcription by inflammatory cytokines

Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York

Submitted 16 September 2003 ; accepted in final form 7 September 2004

Inflammatory cytokines have been shown to inhibit renin gene expression in the kidney in vivo and the kidney tumor-derived As4.1 cell line. In this report, we show that cytokines oncostatin M (OSM), IL-6, and IL-1 inhibit transcriptional activity associated with 4.1 kb of the mouse renin 5'-flanking sequence in As4.1 cells. The 242-bp enhancer (–2866 to –2625 bp) is sufficient to mediate the observed inhibitory effects. Sequences within the enhancer required for inhibition by each of these cytokines have been determined by deletional and mutational analysis. Results indicate that a 39-bp region (CEC) containing a cAMP-responsive element, an E-box, and a steroid receptor-binding site, previously identified as the most critical elements for enhancer activity, is sufficient for the inhibition induced by IL-1. However, mutation of each of the three component sites does not abolish the inhibition by IL-1, suggesting that the target(s) of cytokine action may not be the transcription factors binding directly to these sites. This CEC region is also critical, but not sufficient, for the inhibition mediated by OSM and IL-6. These data suggest that the direct target of the associated cytokines may be coactivators interacting with transcription factors binding at the enhancer. Finally, we show that OSM treatment caused a 17-fold increase in promoter activity when only 2,625 bp of the Ren-1^c flanking sequence were tested, in which the enhancer is not present. Three regions including –2625 to –1217 bp, the HOX·PBX binding site at –60 bp, and –59 to +6 bp have been found to contribute to this induction.

As4.1; oncostatin M; IL-6; IL-1

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