The Met-196 -> Arg variation of human tumor necrosis factor receptor 2 (TNFR2) affects TNF-alpha-induced apoptosis by impaired NF-kappaB signaling and target gene expression.
Tumor necrosis factor-alpha (TNF-alpha)-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-kappaB 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-kappaB-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-alpha stimulation. The findings suggest a common molecular mechanism for the involvement of the TNFR2(196ARG) variant in the etiopathogenesis of different chronic inflammatory disorders.
Till
Andreas
A
Institute of Clinical Molecular Biology at the Christian-Albrechts-University Kiel, Schittenhelmstrasse 12, 24105 Kiel, Germany.
Rosenstiel
Philip
P
Krippner-Heidenreich
Anja
A
Mascheretti-Croucher
Silvia
S
Croucher
Peter J P
PJ
Schäfer
Heiner
H
Scheurich
Peter
P
Seegert
Dirk
D
Schreiber
Stefan
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001120:Arginine / Q000235:genetics* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005347:Fibroblasts; D005786:Gene Expression Regulation / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D015850:Interleukin-6 / Q000032:analysis / Q000378:metabolism; D016209:Interleukin-8 / Q000032:analysis / Q000378:metabolism; D008715:Methionine / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D012995:Solubility; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D016207:Cytokines; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D001120:Arginine; D008715:Methionine