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Int. J. Mol. Sci. 2017, 18(9), 1990; doi:10.3390/ijms18091990

The Role of ERK Signaling in Experimental Autoimmune Encephalomyelitis

Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany
The Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, 234 Herzl Street, 7610001 Rehovot, Israel
Department of Biological Regulation, Weizmann Institute of Science, 234 Herzl Street, 7610001 Rehovot, Israel
These authors contribute equally to this work
Author to whom correspondence should be addressed.
Received: 2 August 2017 / Revised: 10 September 2017 / Accepted: 12 September 2017 / Published: 15 September 2017
(This article belongs to the Special Issue Advances in Multiple Sclerosis 2017)
View Full-Text   |   Download PDF [1640 KB, uploaded 18 September 2017]   |  


Extracellular signal-regulated kinase (ERK) signaling plays a crucial role in regulating immune cell function and has been implicated in autoimmune disorders. To date, all commercially available inhibitors of ERK target upstream components, such as mitogen-activated protein (MAP) kinase/ERK kinase (MEKs), but not ERK itself. Here, we directly inhibit nuclear ERK translocation by a novel pharmacological approach (Glu-Pro-Glu (EPE) peptide), leading to an increase in cytosolic ERK phosphorylation during T helper (Th)17 cell differentiation. This was accompanied by diminished secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine influencing the encephalitogenicity of Th17 cells. Neither the production of the cytokine interleukin (IL)-17 nor the proliferation rate of T cells was affected by the EPE peptide. The in vivo effects of ERK inhibition were challenged in two independent variants of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Overall, ERK inhibition had only a very minor impact on the clinical disease course of EAE. This indicates that while ERK translocation might promote encephalitogenicity in T cells in vitro by facilitating GM-CSF production, this effect is overcome in more complex in vivo animal models of central nervous system (CNS) autoimmunity. View Full-Text
Keywords: T cells; ERK pathway; EPE peptide; experimental autoimmune encephalomyelitis; multiple sclerosis; cell signaling T cells; ERK pathway; EPE peptide; experimental autoimmune encephalomyelitis; multiple sclerosis; cell signaling

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Birkner, K.; Wasser, B.; Loos, J.; Plotnikov, A.; Seger, R.; Zipp, F.; Witsch, E.; Bittner, S. The Role of ERK Signaling in Experimental Autoimmune Encephalomyelitis. Int. J. Mol. Sci. 2017, 18, 1990.

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