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  • Meeting abstract
  • Open Access

Gadd45β-induced prolonged activation of p38 kinase defines a novel pathway mediating negative selection of thymocytes

  • 1,
  • 2,
  • 3,
  • 1 and
  • 2
Cell Communication and Signaling20097 (Suppl 1) :A61

  • Published:


  • Protein Kinase
  • Dexamethasone
  • Caspase Activation
  • Apoptotic Pathway
  • Negative Selection

The clonal deletion of thymocytes by negative selection is an important process to ensure immunologic tolerance, even though the underlying molecular mechanisms are poorly understood. Here, we show that Gadd45β, a regulator of mitogen-activated protein kinases, is critically involved in triggering negative selection. Gadd45β expression was inducible in different models of negative selection. Strikingly, only TCR-ligating peptides resulting in negative selection, but not positively selecting ligands or dexamethasone, a TCR-independent apoptosis agonist, induced Gadd45β expression. Expression of Gadd45β maintained a sustained activation of p38 kinase and thereby promoted TCR-mediated apoptosis. In contrast, inhibition of Gadd45β expression or p38 activity impaired cell death. Moreover, thymocytes from Gadd45β-deficient mice revealed only transient p38 activation, reduced caspase activation and cell death. Thus, we provide evidence that Gadd45β and a resulting persistent activation of p38 constitute a novel apoptotic pathway involved in negative selection.

Authors’ Affiliations

Institute of Molecular Medicine, Heinrich-Heine-University, Düsseldorf, Germany
Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University, Düsseldorf, Germany
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, 3307 N. Broad Street, Philadelphia, USA


© Keil et al; licensee BioMed Central Ltd. 2009

This article is published under license to BioMed Central Ltd.