Rap1a deficiency modifies cytokine responses and MAPK-signaling in vitro and impairs the in vivo inflammatory response.
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.
Department of Pathology, University Medical Centre Freiburg, Freiburg, Germany.
Annette
A
Dorn
Anna
A
Zoellner
Marie
M
Follo
Stefan
S
Martin
Felix
F
Weber
Reinhard
R
Marks
Wolfgang
W
Melchinger
Robert
R
Zeiser
Paul
P
Fisch
Jürgen S
JS
Scheele
D000818:Animals; D016207:Cytokines / Q000276:immunology*; D004789:Enzyme Activation; D007249:Inflammation / Q000276:immunology; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D020827:rap1 GTP-Binding Proteins / Q000172:deficiency / Q000276:immunology*
D016207:Cytokines; D020827:rap1 GTP-Binding Proteins