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J. Biol. Chem., Vol. 280, Issue 10, 9706-9718, March 11, 2005

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MEK1-dependent Delayed Expression of Fos-related Antigen-1 Counteracts c-Fos and p65 NF-B-mediated Interleukin-8 Transcription in Response to Cytokines or Growth Factors^*

Elke Hoffmann, Axel Thiefes, Daniela Buhrow, Oliver Dittrich-Breiholz, Heike Schneider, Klaus Resch, and Michael Kracht

From the Institute of Pharmacology, Medical School Hannover, Carl-Neuberg Strasse 1, D-30625 Hannover, Germany

Binding sites for the dimeric transcription factor activator protein (AP)-1 are found in numerous immunoregulatory and inflammatory genes. The precise mechanisms by which AP-1 activates or represses immune response genes and in particular the roles of individual AP-1 subunits in inflammatory responses are largely unknown. We report here that c-Fos and Fos-related antigen-1 (Fra-1), two inducible components of AP-1, are recruited to the endogenous interleukin (IL)-8 promoter in an IL-1-dependent manner. c-Fos activates IL-8 transcription and synergizes in this effect with p65 NF-B. In contrast, Fra-1 strongly inhibits inducible IL-8 transcription. Fra-1 activation involves its stabilization, ubiquitination, and interaction with histone deacetylase-1. Blockade of MEK1 by PD98059 suppresses c-Fos and Fra-1 expression and, thus, affects two counteractive signals for IL-8 mRNA synthesis simultaneously. This disturbs the inducible recruitment of TATA box-binding protein and RNA polymerase II to the IL-8 promoter. Additional experiments reveal that, in conjunction with p65 NF-B, the MEK1-ERK-dependent synthesis of c-Fos and Fra-1 serves to adjust the overall expression level of IL-8 in response to two of its physiological inducers, IL-1 and epidermal growth factor. Relative to c-Fos, the delayed recruitment of Fra-1 to the IL-8 promoter provides an example how AP-1 subunits may dampen excessive chemokine synthesis.

Received for publication, June 24, 2004 , and in revised form, December 15, 2004.

^* This work was supported by Deutsche Forschungsgemeinschaft Grants KR1143/4-1, KR-1143/4-2, Kr1143/5-1, SFB566/B06, and SFB566/Z02 (to M. K.) and by the Medical School Hannover HILF program (to E. H.). 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.

To whom correspondence should be addressed. Tel.: 49-511-532-2800/2802; Fax: 49-511-532-4081; E-mail: Kracht.Michael{at}MH-Hannover.DE.

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