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

• Published in: The Journal of immunology (1950) 2003-11, Vol.171 (10), p.4984-4989
• Main Authors: Agrawal, Sudhanshu, Agrawal, Anshu, Doughty, Barbara, Gerwitz, Andrew, Blenis, John, Van Dyke, Thomas, Pulendran, Bali
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - pharmacology; Antigens, Helminth; Cells, Cultured; Dendritic Cells - immunology; Dendritic Cells - metabolism; Dipeptides - pharmacology; Escherichia coli - immunology; Flagellin - pharmacology; Helminth Proteins - pharmacology; Humans; Interleukin-12 - antagonists & inhibitors; Interleukin-12 - biosynthesis; Lipopolysaccharides - pharmacology; Lipoproteins - pharmacology; MAP Kinase Signaling System - immunology; Membrane Glycoproteins - agonists; Membrane Glycoproteins - physiology; Mitogen-Activated Protein Kinase 1 - physiology; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinase 8; Mitogen-Activated Protein Kinases - physiology; Monocytes - cytology; Monocytes - immunology; Monocytes - metabolism; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Protein Subunits - antagonists & inhibitors; Protein Subunits - biosynthesis; Proto-Oncogene Proteins c-fos - metabolism; Proto-Oncogene Proteins c-fos - physiology; Receptors, Cell Surface - agonists; Receptors, Cell Surface - physiology; T-Lymphocytes, Helper-Inducer - enzymology; T-Lymphocytes, Helper-Inducer - immunology; T-Lymphocytes, Helper-Inducer - metabolism; Th1 Cells - immunology; Th1 Cells - metabolism; Toll-Like Receptor 2; Toll-Like Receptor 4; Toll-Like Receptor 5; Toll-Like Receptors
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.171.10.4984

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.