Rap1a deficiency modifies cytokine responses and MAPK-signaling in vitro and impairs the in vivo inflammatory response

Cell Immunol. Mar-Apr 2012;276(1-2):187-95. doi: 10.1016/j.cellimm.2012.05.008. Epub 2012 May 23.

Abstract

Rap1, which is closely related to ras, plays a key role in T-cell receptor (TCR)-signaling. TCR-stimulation without costimulation leads to constitutively activated rap1, which may mediate T-cell anergy via inhibition of ras-dependent induction of extracellular signal-regulated kinases (ERK). This activation is mediated by a second protein kinase b-Raf. Rap1-GTP is thought to activate ERK in a ras-independent manner by binding b-raf. Generally, T cells do not express b-raf while they express the adaptor protein raf-1, which is usually sequestered by rap1 leading to inhibition of ras-mediated ERK activation. In this study, we demonstrate that in rap1-deficient T cells, signaling by the ERK and p38 kinases is increased following activation by different stimuli leading to increased intracellular accumulation and secretion of cytokines. In addition, in a hypersensitivity model rap1-deficient mice demonstrated reduced contact dermatitis compared to wildtype mice, demonstrating the impact of rap1-deficiency on the inflammatory response in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytokines / immunology*
  • Enzyme Activation
  • Inflammation / immunology
  • MAP Kinase Signaling System*
  • Mice
  • Mice, Knockout
  • Phenotype
  • rap1 GTP-Binding Proteins / deficiency
  • rap1 GTP-Binding Proteins / immunology*

Substances

  • Cytokines
  • rap1 GTP-Binding Proteins