Abstract
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.
Highlights
Extracellular signal-regulated kinase (ERK) signaling is known to play a crucial role in regulating cellular proliferation, differentiation, and survival [1]
Activation and proliferation of CD4+ T helper cells is crucial for the onset and progression of EAE disease in mice, we first tested whether inhibition of the ERK cascade influences proliferation in peripheral CD4+ splenocytes (Figure 1A)
We show that the secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) in Th17 cells was diminished by the inhibition of the nuclear ERK translocation with the EPE peptide
Summary
Extracellular signal-regulated kinase (ERK) signaling is known to play a crucial role in regulating cellular proliferation, differentiation, and survival [1]. Recent studies suggest a role of the ERK cascade in the innate immune system and in autoimmune responses [6]. Multiple pieces of evidence point to the importance of ERK signaling in T cells, starting from signal transduction from the T cell receptor (TCR) to the G protein Ras and further to downstream components of the kinase cascade, namely, Raf, MEK, and ERK. Given the dominant role of the nuclear function of ERK in mediating proliferation and differentiation, prevention of the nuclear translocation of ERK should inhibit proliferation without affecting the initiation of the negative feedback loops. Studies using peptide inhibitors of translocation prevented nuclear entry of ERKs and resulted in slower growth of various cells without affecting the AKT pathway [18,20]. The potential of the inhibition of ERK translocation in autoimmune neuroinflammation has not been tested so far
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