Pharmacologic inhibition of MEK-ERK signaling enhances Th17 differentiation.
The cytokines and transcription factors that promote Th17 cell development have been extensively studied. However, the signaling pathways that antagonize Th17 differentiation remain poorly characterized. In this study, we report that pharmacologic inhibition of MEK-ERK signaling enhances the in vitro differentiation of Th17 cells and increases their gene expression of il-17a, il-17f, il-21, il-22, and il-23r. IL-2, which suppresses Th17 differentiation via STAT5 activation, also acts through ERK signaling to inhibit Th17 generation. In turn, ERK signaling is found to potentiate the production of IL-2 and activate STAT5, suggesting the existence of an autoregulatory loop to constrain Th17 development. Finally, compared with the transfer of untreated Th17 cells, the transfer of ERK-inhibited Th17 cells leads to accelerated onset and exacerbated colitis in immunodeficient mice. Our data indicate that MEK-ERK signaling negatively regulates Th17 differentiation in a Th cell-intrinsic manner.
Tan
Andy Hee-Meng
AH
Immunology Group, Bioprocessing Technology Institute, Centros, Singapore.
Lam
Kong-Peng
KP
D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000637:transplantation
D002070:Butadienes; C098680:Il17a protein, mouse; D020381:Interleukin-17; D009570:Nitriles; D047428:Protein Kinase Inhibitors; C113580:U 0126; D048049:Extracellular Signal-Regulated MAP Kinases