title: A Toll-like receptor 2 ligand stimulates Th2 responses in vivo, via induction of extracellular signal-regulated kinase mitogen-activated protein kinase and c-Fos in dendritic cells.
abstract: The adaptive immune system can generate distinct classes of responses, but the mechanisms that determine this are poorly understood. In this study, we demonstrate that different Toll-like receptor (TLR) ligands induce distinct dendritic cell (DC) activation and immune responses in vivo. Thus, Escherichia coli LPS (TLR-4 stimulus), activates DCs to produce abundant IL-12(p70), but little IL-10, and stimulates Th1 and Tc1 responses. In contrast, Pam-3-cys (TLR-2 stimulus) elicits less IL-12(p70), but abundant IL-10, and favors Th2 and T cytotoxic 2 (Tc2) responses. These distinct responses likely occur via differences in extracellular signal-regulated kinase signaling in DCs. Thus, Pam-3-cys induces enhanced extracellular signal-regulated kinase signaling, compared with LPS, resulting in suppressed IL-12(p70) and enhanced IL-10 production, as well as enhanced induction of the transcription factor, c-Fos. Interestingly, DCs from c-fos(-/-) mice produce more IL-12(p70), but less IL-10, compared with control DCs. Therefore, different TLR ligands induce distinct cytokines and signaling in DCs, and differentially bias Th responses in vivo.
authors.affiliation: Vaccine Research Center, Emory University, Atlanta, GA 30329, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Dillon
authors.forename: Anshu
authors.initials: A
authors.lastname: Agrawal
authors.forename: Thomas
authors.initials: T
authors.lastname: Van Dyke
authors.forename: Gary
authors.initials: G
authors.lastname: Landreth
authors.forename: Laurie
authors.initials: L
authors.lastname: McCauley
authors.forename: Amy
authors.initials: A
authors.lastname: Koh
authors.forename: Charles
authors.initials: C
authors.lastname: Maliszewski
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Bali
authors.initials: B
authors.lastname: Pulendran
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000502:physiology; D039481:CD11b Antigen / Q000378:metabolism; D039521:CD11c Antigen / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D004151:Dipeptides / Q000378:metabolism / Q000494:pharmacology; D004790:Enzyme Induction / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D004926:Escherichia coli / Q000276:immunology; D017781:Genes, Immediate-Early / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008024:Ligands; D008070:Lipopolysaccharides / Q000378:metabolism / Q000494:pharmacology; D008074:Lipoproteins / Q000378:metabolism / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D053594:Myeloid Differentiation Factor 88; D010047:Ovalbumin / Q000276:immunology; D010766:Phosphorylation; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis* / Q000502:physiology; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism*; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D039481:CD11b Antigen; D039521:CD11c Antigen; D004151:Dipeptides; D018984:Epitopes, T-Lymphocyte; D008024:Ligands; D008070:Lipopolysaccharides; D008074:Lipoproteins; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D021122:Protein Subunits; D016760:Proto-Oncogene Proteins c-fos; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D016753:Interleukin-10; D018664:Interleukin-12; D010047:Ovalbumin; C047210:2,3-bis-(palmitoyloxy)-2-propyl-N-palmitoyl-cysteinylserine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases