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
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, Escher...
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| Veröffentlicht in: | The Journal of immunology (1950) 2004-04, Vol.172 (8), p.4733-4743 |
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| container_title | The Journal of immunology (1950) |
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| creator | Dillon, Stephanie Agrawal, Anshu Van Dyke, Thomas Landreth, Gary McCauley, Laurie Koh, Amy Maliszewski, Charles Akira, Shizuo Pulendran, Bali |
| description | 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. |
| doi_str_mv | 10.4049/jimmunol.172.8.4733 |
| format | Article |
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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.</description><identifier>ISSN: 0022-1767</identifier><identifier>EISSN: 1550-6606</identifier><identifier>DOI: 10.4049/jimmunol.172.8.4733</identifier><identifier>PMID: 15067049</identifier><language>eng</language><publisher>United States: Am Assoc Immnol</publisher><subject>Adaptor Proteins, Signal Transducing ; Animals ; Antigens, Differentiation - genetics ; Antigens, Differentiation - physiology ; CD11b Antigen - metabolism ; CD11c Antigen - biosynthesis ; CD4-Positive T-Lymphocytes - immunology ; CD4-Positive T-Lymphocytes - metabolism ; Dendritic Cells - enzymology ; Dendritic Cells - immunology ; Dendritic Cells - metabolism ; Dipeptides - metabolism ; Dipeptides - pharmacology ; Enzyme Induction - immunology ; Epitopes, T-Lymphocyte - immunology ; Escherichia coli ; Escherichia coli - immunology ; Genes, Immediate-Early - immunology ; Interleukin-10 - biosynthesis ; Interleukin-12 - antagonists & inhibitors ; Interleukin-12 - biosynthesis ; Ligands ; Lipopolysaccharides - metabolism ; Lipopolysaccharides - pharmacology ; Lipoproteins - metabolism ; Lipoproteins - pharmacology ; Male ; MAP Kinase Signaling System - immunology ; Membrane Glycoproteins - deficiency ; Membrane Glycoproteins - genetics ; Membrane Glycoproteins - metabolism ; Membrane Glycoproteins - physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Mitogen-Activated Protein Kinase 1 - metabolism ; Mitogen-Activated Protein Kinase 3 ; Mitogen-Activated Protein Kinases - biosynthesis ; Mitogen-Activated Protein Kinases - deficiency ; Mitogen-Activated Protein Kinases - genetics ; Mitogen-Activated Protein Kinases - metabolism ; Mitogen-Activated Protein Kinases - physiology ; Myeloid Differentiation Factor 88 ; Ovalbumin - immunology ; Phosphorylation ; Protein Subunits - antagonists & inhibitors ; Protein Subunits - biosynthesis ; Proto-Oncogene Proteins c-fos - biosynthesis ; Proto-Oncogene Proteins c-fos - physiology ; Receptors, Cell Surface - deficiency ; Receptors, Cell Surface - genetics ; Receptors, Cell Surface - metabolism ; Receptors, Cell Surface - physiology ; Receptors, Immunologic - deficiency ; Receptors, Immunologic - genetics ; Receptors, Immunologic - physiology ; Spleen - cytology ; Spleen - immunology ; Th2 Cells - immunology ; Th2 Cells - metabolism ; Toll-Like Receptor 2 ; Toll-Like Receptor 4 ; Toll-Like Receptors</subject><ispartof>The Journal of immunology (1950), 2004-04, Vol.172 (8), p.4733-4743</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c475t-25485a131ecfc82e85b329822800d8bdf171e36a22ccd284350dfd1039cf89423</citedby><cites>FETCH-LOGICAL-c475t-25485a131ecfc82e85b329822800d8bdf171e36a22ccd284350dfd1039cf89423</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15067049$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dillon, Stephanie</creatorcontrib><creatorcontrib>Agrawal, Anshu</creatorcontrib><creatorcontrib>Van Dyke, Thomas</creatorcontrib><creatorcontrib>Landreth, Gary</creatorcontrib><creatorcontrib>McCauley, Laurie</creatorcontrib><creatorcontrib>Koh, Amy</creatorcontrib><creatorcontrib>Maliszewski, Charles</creatorcontrib><creatorcontrib>Akira, Shizuo</creatorcontrib><creatorcontrib>Pulendran, Bali</creatorcontrib><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</title><title>The Journal of immunology (1950)</title><addtitle>J Immunol</addtitle><description>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.</description><subject>Adaptor Proteins, Signal Transducing</subject><subject>Animals</subject><subject>Antigens, Differentiation - genetics</subject><subject>Antigens, Differentiation - physiology</subject><subject>CD11b Antigen - metabolism</subject><subject>CD11c Antigen - biosynthesis</subject><subject>CD4-Positive T-Lymphocytes - immunology</subject><subject>CD4-Positive T-Lymphocytes - metabolism</subject><subject>Dendritic Cells - enzymology</subject><subject>Dendritic Cells - immunology</subject><subject>Dendritic Cells - metabolism</subject><subject>Dipeptides - metabolism</subject><subject>Dipeptides - pharmacology</subject><subject>Enzyme Induction - immunology</subject><subject>Epitopes, T-Lymphocyte - immunology</subject><subject>Escherichia coli</subject><subject>Escherichia coli - immunology</subject><subject>Genes, Immediate-Early - immunology</subject><subject>Interleukin-10 - biosynthesis</subject><subject>Interleukin-12 - antagonists & inhibitors</subject><subject>Interleukin-12 - biosynthesis</subject><subject>Ligands</subject><subject>Lipopolysaccharides - metabolism</subject><subject>Lipopolysaccharides - pharmacology</subject><subject>Lipoproteins - metabolism</subject><subject>Lipoproteins - pharmacology</subject><subject>Male</subject><subject>MAP Kinase Signaling System - immunology</subject><subject>Membrane Glycoproteins - deficiency</subject><subject>Membrane Glycoproteins - genetics</subject><subject>Membrane Glycoproteins - metabolism</subject><subject>Membrane Glycoproteins - physiology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Mice, Transgenic</subject><subject>Mitogen-Activated Protein Kinase 1 - metabolism</subject><subject>Mitogen-Activated Protein Kinase 3</subject><subject>Mitogen-Activated Protein Kinases - biosynthesis</subject><subject>Mitogen-Activated Protein Kinases - deficiency</subject><subject>Mitogen-Activated Protein Kinases - genetics</subject><subject>Mitogen-Activated Protein Kinases - metabolism</subject><subject>Mitogen-Activated Protein Kinases - physiology</subject><subject>Myeloid Differentiation Factor 88</subject><subject>Ovalbumin - immunology</subject><subject>Phosphorylation</subject><subject>Protein Subunits - antagonists & inhibitors</subject><subject>Protein Subunits - biosynthesis</subject><subject>Proto-Oncogene Proteins c-fos - biosynthesis</subject><subject>Proto-Oncogene Proteins c-fos - physiology</subject><subject>Receptors, Cell Surface - deficiency</subject><subject>Receptors, Cell Surface - genetics</subject><subject>Receptors, Cell Surface - metabolism</subject><subject>Receptors, Cell Surface - physiology</subject><subject>Receptors, Immunologic - deficiency</subject><subject>Receptors, Immunologic - genetics</subject><subject>Receptors, Immunologic - physiology</subject><subject>Spleen - cytology</subject><subject>Spleen - immunology</subject><subject>Th2 Cells - immunology</subject><subject>Th2 Cells - metabolism</subject><subject>Toll-Like Receptor 2</subject><subject>Toll-Like Receptor 4</subject><subject>Toll-Like Receptors</subject><issn>0022-1767</issn><issn>1550-6606</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU-PEyEchonRuHX1E5gYTnpxKn9mBubY1F3dWKPZrV4JZZgpKwNdYFr9Xn5AmW03evNEfvC8D4EXgJcYzUtUNu9uzTCMzts5ZmTO5yWj9BGY4apCRV2j-jGYIURIgVnNzsCzGG8RQjUi5VNwhitUs-yYgd8LuPbWFivzQ8NrrfQu-QAJXJleuhbeJDOMViYd4XpLMhB33sU8XTn43ez9W7g3Mg_tqJLxDvoOXvxMQSptbc4FeGN6J21xrft7TQs_GSejhp9N8r12xSLn9vcHX4NP2rgHYLpdFZc-wrz3Xrs2mGQUXGZxfA6edNJG_eK0noNvlxfr5cdi9eXD1XKxKlTJqlSQquSVxBRr1SlONK82lDScEI5QyzdthxnWtJaEKNUSXtIKtV2LEW1Ux5uS0HPw-ujdBX836pjEYOL0NOm0H6NgmKOG5n__H4hZQxjCE0iPoAo-xqA7sQtmkOGXwEhMrYqHVnOGCC6mVnPq1Uk_bgbd_s2caszAmyOwNf32YIIWcZDWZhyLw-Hwj-oPWJ-uqg</recordid><startdate>20040415</startdate><enddate>20040415</enddate><creator>Dillon, Stephanie</creator><creator>Agrawal, Anshu</creator><creator>Van Dyke, Thomas</creator><creator>Landreth, Gary</creator><creator>McCauley, Laurie</creator><creator>Koh, Amy</creator><creator>Maliszewski, Charles</creator><creator>Akira, Shizuo</creator><creator>Pulendran, Bali</creator><general>Am Assoc Immnol</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20040415</creationdate><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</title><author>Dillon, Stephanie ; Agrawal, Anshu ; Van Dyke, Thomas ; Landreth, Gary ; McCauley, Laurie ; Koh, Amy ; Maliszewski, Charles ; Akira, Shizuo ; Pulendran, Bali</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c475t-25485a131ecfc82e85b329822800d8bdf171e36a22ccd284350dfd1039cf89423</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Adaptor Proteins, Signal Transducing</topic><topic>Animals</topic><topic>Antigens, Differentiation - genetics</topic><topic>Antigens, Differentiation - physiology</topic><topic>CD11b Antigen - metabolism</topic><topic>CD11c Antigen - biosynthesis</topic><topic>CD4-Positive T-Lymphocytes - immunology</topic><topic>CD4-Positive T-Lymphocytes - metabolism</topic><topic>Dendritic Cells - enzymology</topic><topic>Dendritic Cells - immunology</topic><topic>Dendritic Cells - metabolism</topic><topic>Dipeptides - metabolism</topic><topic>Dipeptides - pharmacology</topic><topic>Enzyme Induction - immunology</topic><topic>Epitopes, T-Lymphocyte - immunology</topic><topic>Escherichia coli</topic><topic>Escherichia coli - immunology</topic><topic>Genes, Immediate-Early - immunology</topic><topic>Interleukin-10 - biosynthesis</topic><topic>Interleukin-12 - antagonists & inhibitors</topic><topic>Interleukin-12 - biosynthesis</topic><topic>Ligands</topic><topic>Lipopolysaccharides - metabolism</topic><topic>Lipopolysaccharides - pharmacology</topic><topic>Lipoproteins - metabolism</topic><topic>Lipoproteins - pharmacology</topic><topic>Male</topic><topic>MAP Kinase Signaling System - immunology</topic><topic>Membrane Glycoproteins - deficiency</topic><topic>Membrane Glycoproteins - genetics</topic><topic>Membrane Glycoproteins - metabolism</topic><topic>Membrane Glycoproteins - physiology</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Mice, Transgenic</topic><topic>Mitogen-Activated Protein Kinase 1 - metabolism</topic><topic>Mitogen-Activated Protein Kinase 3</topic><topic>Mitogen-Activated Protein Kinases - biosynthesis</topic><topic>Mitogen-Activated Protein Kinases - deficiency</topic><topic>Mitogen-Activated Protein Kinases - genetics</topic><topic>Mitogen-Activated Protein Kinases - metabolism</topic><topic>Mitogen-Activated Protein Kinases - physiology</topic><topic>Myeloid Differentiation Factor 88</topic><topic>Ovalbumin - immunology</topic><topic>Phosphorylation</topic><topic>Protein Subunits - antagonists & inhibitors</topic><topic>Protein Subunits - 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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.</abstract><cop>United States</cop><pub>Am Assoc Immnol</pub><pmid>15067049</pmid><doi>10.4049/jimmunol.172.8.4733</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adaptor Proteins, Signal Transducing Animals Antigens, Differentiation - genetics Antigens, Differentiation - physiology CD11b Antigen - metabolism CD11c Antigen - biosynthesis CD4-Positive T-Lymphocytes - immunology CD4-Positive T-Lymphocytes - metabolism Dendritic Cells - enzymology Dendritic Cells - immunology Dendritic Cells - metabolism Dipeptides - metabolism Dipeptides - pharmacology Enzyme Induction - immunology Epitopes, T-Lymphocyte - immunology Escherichia coli Escherichia coli - immunology Genes, Immediate-Early - immunology Interleukin-10 - biosynthesis Interleukin-12 - antagonists & inhibitors Interleukin-12 - biosynthesis Ligands Lipopolysaccharides - metabolism Lipopolysaccharides - pharmacology Lipoproteins - metabolism Lipoproteins - pharmacology Male MAP Kinase Signaling System - immunology Membrane Glycoproteins - deficiency Membrane Glycoproteins - genetics Membrane Glycoproteins - metabolism Membrane Glycoproteins - physiology Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Mitogen-Activated Protein Kinase 1 - metabolism Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinases - biosynthesis Mitogen-Activated Protein Kinases - deficiency Mitogen-Activated Protein Kinases - genetics Mitogen-Activated Protein Kinases - metabolism Mitogen-Activated Protein Kinases - physiology Myeloid Differentiation Factor 88 Ovalbumin - immunology Phosphorylation Protein Subunits - antagonists & inhibitors Protein Subunits - biosynthesis Proto-Oncogene Proteins c-fos - biosynthesis Proto-Oncogene Proteins c-fos - physiology Receptors, Cell Surface - deficiency Receptors, Cell Surface - genetics Receptors, Cell Surface - metabolism Receptors, Cell Surface - physiology Receptors, Immunologic - deficiency Receptors, Immunologic - genetics Receptors, Immunologic - physiology Spleen - cytology Spleen - immunology Th2 Cells - immunology Th2 Cells - metabolism Toll-Like Receptor 2 Toll-Like Receptor 4 Toll-Like Receptors |
| 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 |
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