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Peptide-Mediated Disruption of NFB/NRF Interaction Inhibits IL-8 Gene Activation by IL-1 or Helicobacter pylori¹

Myriam Bartels^*, Aike Torben Schweda^*, Ursula Dreikhausen^*, Ronald Frank, Klaus Resch^*, Winfried Beil^* and Mahtab Nourbakhsh^2,*

^* Institute of Pharmacology, Hannover Medical School, Hannover, Germany; and Department of Chemical Biology Helmholtz, Centre for Infection Research, Braunschweig, Germany

Selective inhibition of proinflammatory chemokines such as IL-8 is an important approach to combat inflammatory and infection diseases. Previous studies suggested that interaction of transcription factors NFB repressing factor (NRF) and NFB play a crucial role in activation of IL-8 gene expression. In a search for a specific inhibitor of IL-8 expression, we applied tandem affinity purification to investigate interaction of NRF and NFB p65 in cells. We identified a synthetic peptide corresponding to aa 223–238 of NRF interfering with binding of endogenous p65 to NRF. Furthermore, nucleofection experiments were established to introduce this inhibitory peptide into the nucleus of IL-1 stimulated human cervical and Helicobacter pylori infected gastric epithelial cells. Our data clearly show that the specific peptide disturbing NRF/NFB interaction is able to significantly decrease endogenous IL-8 gene transcription in response to IL-1 or Helicobacter pylori infection. Thus, our study provides novel insights into NRF and NFB interaction in vivo and may facilitate the design of new anti-IL-8 drugs based on novel strategies.

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 This work was supported by grants from "Deutsche Forschungsgemeinschaft", DFG457 and SFB566.

² Address correspondence and reprint requests to Dr. Mahtab Nourbakhsh, Institute of Pharmacology, Hannover Medical School, OE 5320, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany. E-mail address: nourbakhsh.mahtab{at}mh-hannover.de

³ Abbreviations used in this paper: NRF, NFB repressing factor; iNOS, inducible NO synthase; HeLa, human cervical cell; TAP, tandem affinity purification; AGS, gastric epithelial cell; CBP, calmodulin binding peptide; TEV, tobacco etch virus; RHD, Rel homology domain; ChIP, chromatin immunoprecipitation; wt, wild type.