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J. Biol. Chem., Vol. 280, Issue 51, 42113-42123, December 23, 2005

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The Transcription Factors AP-1 and Ets Are Regulators of C3a Receptor Expression^*

Myriam Schaefer, Stephanie Konrad, Jessica Thalmann, Claudia Rheinheimer, Kay Johswich, Bettina Sohns, and Andreas Klos1

From the Department of Medical Microbiology, Medical School Hannover (MHH), Carl-Neubergstrasse 1, D-30625 Hannover, Germany and LEBAO, Podbielskistrasse 380, 30659 Hannover, Germany

The anaphylatoxin C3a is a proinflammatory mediator generated during complement activation. The tight control of C3a receptor (C3aR) expression is crucial for the regulation of anaphylatoxin-mediated effects. Key factors regulating constitutive expression of the C3aR in the mast cell line HMC-1 and receptor induction by dibutyryl-cAMP in monomyeloblastic U937 cells were determined by functional characterization of the C3aR promoter. Nucleotides -18 to -285 upstream of the translational start site proved to be critical for promoter activity in HMC-1 cells. Binding sites for the transcription factors AP-1 and Ets could be located. Overexpressed c-Jun/c-Fos (AP-1) and Ets-1 led synergistically to increased promoter activity that was substantially reduced by site-directed mutagenesis of the corresponding elements within the C3aR promoter. In HMC-1 cells, Ets interacted directly with the predicted binding motif of the C3aR promoter as determined by electromobility shift assays. AP-1 binding to the C3aR promoter was augmented during C3aR induction in U937 cells. A retroviral gene transfer system was used to express a dominant negative mutant of Ets-1 in these cells. The resulting cells failed to up-regulate the C3aR after stimulation with dibutyryl-cAMP and showed decreased AP-1 binding, suggesting that Ets acts here indirectly. Thus, it was established that Ets and the AP-1 element mediates dibutyryl-cAMP induction of C3aR promoter activity, hence providing a mechanistic explanation of dibutyryl-cAMP-dependent up-regulation of C3aR expression. In conclusion, this study demonstrates an important role of AP-1 and a member of the Ets family in the transcriptional regulation of C3aR expression, a prerequisite for the ability of C3a to participate in immunomodulation and inflammation.

Received for publication, July 26, 2005 , and in revised form, September 26, 2005.

^* This work was financed by Deutsche Forschungsgemeinschaft Grant SFB 566/A04. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 49-511-532-4342; Fax: 49-511-532-4366; E-mail: Klos.Andreas{at}mh-hannover.de.

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