Cutting edge: different Toll-like receptor agonists instruct dendritic cells to induce distinct Th responses via differential modulation of extracellular signal-regulated kinase-mitogen-activated protein kinase and c-Fos.
Dendritic cells (DCs) are pivotal in determining the class of an adaptive immune response. However, the molecular mechanisms within DCs that determine this decision-making process are unknown. Here, we demonstrate that distinct Toll-like receptor (TLR) ligands instruct human DCs to induce distinct Th cell responses by differentially modulating mitogen-activated protein kinase signaling. Thus, Escherichia coli LPS and flagellin, which trigger TLR4 and TLR5, respectively, instruct DCs to stimulate Th1 responses via IL-12p70 production, which depends on the phosphorylation of p38 and c-Jun N-terminal kinase 1/2. In contrast, the TLR2 agonist, Pam3cys, and the Th2 stimulus, schistosome egg Ags: 1) barely induce IL-12p70; 2) stimulate sustained duration and magnitude of extracellular signal-regulated kinase 1/2 phosphorylation, which results in stabilization of the transcription factor c-Fos, a suppressor of IL-12; and 3) yield a Th2 bias. Thus, distinct TLR agonists differentially modulate extracellular signal-regulated kinase signaling, c-Fos activity, and cytokine responses in DCs to stimulate different Th responses.
Agrawal
Sudhanshu
S
Emory Vaccine Center, Atlanta, GA 30329, USA.
Agrawal
Anshu
A
Doughty
Barbara
B
Gerwitz
Andrew
A
Blenis
John
J
Van Dyke
Thomas
T
Pulendran
Bali
B
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000947:Antigens, Helminth; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D004926:Escherichia coli / Q000276:immunology; D005408:Flagellin / Q000494:pharmacology; D015801:Helminth Proteins / Q000494:pharmacology; D006801:Humans; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008074:Lipoproteins / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000819:agonists* / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000819:agonists* / Q000502:physiology*; D006377:T-Lymphocytes, Helper-Inducer / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051198:Toll-Like Receptor 5; D051193:Toll-Like Receptors; D048051:p38 Mitogen-Activated Protein Kinases
D000276:Adjuvants, Immunologic; D000947:Antigens, Helminth; D004151:Dipeptides; D015801:Helminth Proteins; D008070:Lipopolysaccharides; D008074:Lipoproteins; D008562:Membrane Glycoproteins; D021122:Protein Subunits; D016760:Proto-Oncogene Proteins c-fos; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C495346:TLR5 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051198:Toll-Like Receptor 5; D051193:Toll-Like Receptors; C079442:gp50 protein, Schistosoma; D005408:Flagellin; D018664:Interleukin-12; C047210:2,3-bis-(palmitoyloxy)-2-propyl-N-palmitoyl-cysteinylserine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases