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J. Biol. Chem., Vol. 280, Issue 7, 5994-6004, February 18, 2005

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The Met-196 Arg Variation of Human Tumor Necrosis Factor Receptor 2 (TNFR2) Affects TNF--induced Apoptosis by Impaired NF-B Signaling and Target Gene Expression^*

Andreas Till, Philip Rosenstiel, Anja Krippner-Heidenreich¶, Silvia Mascheretti-Croucher, Peter J. P. Croucher, Heiner Schäfer||, Peter Scheurich¶, Dirk Seegert**, and Stefan Schreiber

From the Institute of Clinical Molecular Biology at the Christian-Albrechts-University Kiel, Schittenhelmstrasse 12, 24105 Kiel, Germany, the ^¶Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, Stuttgart, 70569 Germany, the ^||Laboratory of Molecular Gastroenterology, Department of General Internal Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Schittenhelmstrasse 12, 24105 Kiel, Germany and the ^**CONARIS Research Institute AG, Schauenburgerstrasse 116, 24118 Kiel, Germany

Tumor necrosis factor- (TNF-)-induced signaling is pivotally involved in the pathogenesis of chronic inflammatory diseases. A polymorphism in the TNF receptor 2 (TNFR2) gene resulting in a juxtamembrane inversion from methionine (TNFR2^196MET) to arginine (TNFR2^196ARG) has been genetically associated with an increased risk for systemic lupus erythematosus and familial rheumatoid arthritis. Albeit the mutation does not affect the TNF binding kinetics of TNFR2, the present study provides evidence that the mutation results in a significantly lower capability to induce TNFR2-mediated NF-B activation. Pretriggering of TNFR2 with a receptor-specific mutein leads to an enhancement of TNFR1-induced apoptosis, which is further increased in cells carrying the TNFR2^196ARG variant. A diminished induction of NF-B-dependent target genes conveying either anti-apoptotic or pro-inflammatory functions, such as cIAP1, TRAF1, IL-6, or IL-8 is observed. The mutated form TNFR2^196ARG shows a reduction of inducible TRAF2 recruitment upon TNF- stimulation. The findings suggest a common molecular mechanism for the involvement of the TNFR2^196ARG variant in the etiopathogenesis of different chronic inflammatory disorders.

Received for publication, October 12, 2004 , and in revised form, November 9, 2004.

^* This work was supported by Grants SFB415 and SFB495 from the Deutsche Forschungsgemeinschaft, by the competence network IBD (Federal Ministry of Education and Research (BMBF)), and by the National Genome Research Network (NGFN). 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.

These authors contributed equally to the present work.

These authors share senior authorship.

To whom correspondence and reprint requests should be addressed. Tel.: 49-431-597-2350 (or -1279); Fax: 49-431-597-1842; E-mail: s.schreiber{at}mucosa.de.

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