Pharmacologic Inhibition of MEK–ERK Signaling Enhances Th17 Differentiation

Tan, Andy Hee-Meng; Lam, Kong-Peng

doi:10.4049/jimmunol.0901509

Cited by 45 publications

(45 citation statements)

References 47 publications

(48 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nevertheless, the roles of ERK signaling in the regulation of Th17 development have become controversial. Inhibition of ERK in T cells by U0126 was reported to promote Th17 cell development under Th17 conditions (54). In contrast, a recent study by Liu et al (24) demonstrated that blockage of T cell-intrinsic ERK signaling, using ERK inhibitor PD98059 or U0126, leads to reduced Th17 responses.…”

Section: Discussionmentioning

confidence: 79%

TLR7 Engagement on Dendritic Cells Enhances Autoreactive Th17 Responses via Activation of ERK

Xiao

Sun

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

In this study, we showed that TLR7 activation significantly promoted interphotoreceptor retinoid-binding protein (IRBP)-specific Th17 responses by upregulating RORγt, IL-17, GM-CSF, and IL-23R expression in experimental autoimmune uveitis mice. In vivo administration of CL097 activated dendritic cells (DCs) and endowed them with an increased ability to activate IRBP-specific Th17 cells. CL097-treated DCs (CL097-DCs) formed a cytokine milieu that favored the generation and maintenance of Th17 cells by stimulating IL-1β, IL-6, and IL-23 expression. Furthermore, IRBP-specific T cells from immunized mice injected with CL097-DCs produced more IL-17 and transferred more severe experimental autoimmune uveitis than did those from mice injected with DCs. The enhanced immunostimulatory activities of CL097-DCs depended on JNK, ERK, and p38 activation. Blockade of ERK, but not p38 or JNK, completely abolished the Th17 responses induced by CL097-DCs. Collectively, our findings suggest that CL097 treatment significantly promotes autoreactive IL-17+ T cell responses through enhancing DC activation, which is mediated, at least in part, via the activation of ERK signaling.

show abstract

Section: Discussionmentioning

confidence: 79%

TLR7 Engagement on Dendritic Cells Enhances Autoreactive Th17 Responses via Activation of ERK

Xiao

Sun

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…S4h,i). Of note, Erk1/2 inhibition has been previously shown to enhance Th17 cell differentiation (Tan and Lam, 2010) and Erk1/2 phosphorylation has been linked to the reduced expression of REV-ERB proteins (Castellano et al, 2014; Kojetin and Burris, 2014), but the mechanism involved and its relevance for T cells has not been characterized yet. Through a bioinformatic analysis of the nr1d1 promoter we identified a binding site for the CAAT/enhancer-binding protein α (C/EBPα), a leucine zipper transcription factor involved in the regulation of cellular differentiation (Lekstrom-Himes and Xanthopoulos, 1998).…”

Section: Resultsmentioning

confidence: 99%

Melatonin Contributes to the Seasonality of Multiple Sclerosis Relapses

Farez

Mascanfroni

Méndez-Huergo

et al. 2015

Cell

267

215

View full text Add to dashboard Cite

SUMMARY Seasonal changes in disease activity have been observed in multiple sclerosis, an autoimmune disorder that affects the central nervous system. These epidemiological observations suggest that environmental factors influence the disease course. Here we report that melatonin levels, whose production is modulated by seasonal variations in night length, negatively correlate with multiple sclerosis activity in humans. Treatment with melatonin ameliorates disease in an experimental model of multiple sclerosis and directly interferes with the differentiation of human and mouse T cells. Melatonin induces the expression of the repressor transcription factor Nfil3, blocking the differentiation of pathogenic Th17 cells as well as boosts the generation of protective Tr1 cells via Erk1/2 and the transactivation of the IL-10 promoter by ROR-α. These results suggest that melatonin is another example of how environmental-driven cues can impact on T cell differentiation and have implications for autoimmune disorders such as multiple sclerosis.

show abstract

“…One group has reported that the p38 and JNK pathway is important for IL-17A production, based on experiments with pharmacological inhibitors (Lu et al, 2010). Another group has reported that the ERK pathway negatively regulates IL-17A production (Tan and Lam, 2010). Furthermore, it has been reported that JNK1-deficient (Mapk8 À/À ) mice were resistant to EAE (Tran et al, 2006).…”

Section: Discussionmentioning

confidence: 97%

Transcription Factor Smad-Independent T Helper 17 Cell Induction by Transforming-Growth Factor-β Is Mediated by Suppression of Eomesodermin

et al. 2011

View full text Add to dashboard Cite

Transforming growth factor-β (TGF-β) has been shown to be required for Th17 cell differentiation via Smad-independent mechanisms. The molecular mechanism underlying this pathway remains to be clarified, however. We searched for genes regulated by TGF-β through the Smad-independent pathway by using Smad2 and Smad3 double-deficient T cells and identified the transcription factor Eomesodermin (Eomes), whose expression was suppressed by TGF-β via the c-Jun N-terminal kinase (JNK)-c-Jun signaling pathway. Inhibition of JNK strongly suppressed disease in an in vivo EAE model as well as in vitro Th17 cell induction. Overexpression of Eomes substantially suppressed Th17 cell differentiation, whereas ablation of Eomes expression could substitute for TGF-β in Th17 cell induction in primary T cells. Eomes suppressed Rorc and Il17a promoters by directly binding to the proximal region of these promoters. In conclusion, the suppression of Eomes by TGF-β via the JNK pathway is an important mechanism for Smad-independent Th17 cell differentiation.

show abstract

Pharmacologic Inhibition of MEK–ERK Signaling Enhances Th17 Differentiation

Cited by 45 publications

References 47 publications

TLR7 Engagement on Dendritic Cells Enhances Autoreactive Th17 Responses via Activation of ERK

TLR7 Engagement on Dendritic Cells Enhances Autoreactive Th17 Responses via Activation of ERK

Melatonin Contributes to the Seasonality of Multiple Sclerosis Relapses

Transcription Factor Smad-Independent T Helper 17 Cell Induction by Transforming-Growth Factor-β Is Mediated by Suppression of Eomesodermin

Contact Info

Product

Resources

About