Synergistic activation of innate immunity by double-stranded RNA and CpG dna promotes enhanced antitumor activity
Double-stranded RNA (dsRNA) and unmethylated CpG sequences in DNA are pathogen-associated molecular patterns of viruses and bacteria that activate innate immunity. To examine whether dsRNA and CpG DNA could combine to provide enhanced stimulation of innate immune cells, murine macrophages were stimu...
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description | Double-stranded RNA (dsRNA) and unmethylated CpG sequences in DNA are pathogen-associated molecular patterns of viruses and bacteria that activate innate immunity. To examine whether dsRNA and CpG DNA could combine to provide enhanced stimulation of innate immune cells, murine macrophages were stimulated with poly-rI:rC (pIC), a dsRNA analog, and CpG-containing oligodeoxynucleotides (CpG-ODN). Combined treatments demonstrated synergy in nitric oxide, interleukin (IL)-12, tumor necrosis factor alpha, and IL-6 production. Studies using neutralizing antibodies for type I interferons (IFNs), IFN-alpha and IFN-beta, indicated that nitric oxide synthase synergism is mediated by paracrine/autocrine effects of IFN-beta. In contrast, enhanced cytokine production occurred independent of type I IFN and was maintained in macrophages from IFN-alpha/beta receptor knockout mice. Cotransfection of human Toll-like receptors 3 and 9 (receptors for dsRNA and CpG DNA, respectively) into 293T cells supported synergistic activation of an IL-8 promoter reporter construct by pIC, indicating interaction of the signaling pathways in driving the synergy response. In vivo stimulation of mice with pIC and CpG-ODN demonstrated synergy for serum IL-6 and IL-12p40 levels that correlated with an enhanced antitumor effect against established B16-F10 experimental pulmonary metastases. Treatment of tumor-bearing mice with pIC and CpG-ODN in combination resulted in enhanced nitric oxide synthase expression in lung tissue and enhanced up-regulation of class I major histocompatibility complex on splenic dendritic cells relative to treatments with either agent alone. In conclusion, the combined detection of viral pathogen-associated molecular patterns, i.e., dsRNA and CpG DNA, may mimic definitive viral recognition, resulting in an enhanced innate immune response that could be used for tumor vaccination or immunotherapy. |
doi_str_mv | 10.1158/0008-5472.CAN-04-0063 |
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G</creator><creatorcontrib>WHITMORE, Mark M ; DEVEER, Michael J ; EDLING, Andrea ; OATES, Rhonda K ; SIMONS, Brenna ; LINDNER, Daniel ; WILLIAMS, Bryan R. G</creatorcontrib><description>Double-stranded RNA (dsRNA) and unmethylated CpG sequences in DNA are pathogen-associated molecular patterns of viruses and bacteria that activate innate immunity. To examine whether dsRNA and CpG DNA could combine to provide enhanced stimulation of innate immune cells, murine macrophages were stimulated with poly-rI:rC (pIC), a dsRNA analog, and CpG-containing oligodeoxynucleotides (CpG-ODN). Combined treatments demonstrated synergy in nitric oxide, interleukin (IL)-12, tumor necrosis factor alpha, and IL-6 production. Studies using neutralizing antibodies for type I interferons (IFNs), IFN-alpha and IFN-beta, indicated that nitric oxide synthase synergism is mediated by paracrine/autocrine effects of IFN-beta. In contrast, enhanced cytokine production occurred independent of type I IFN and was maintained in macrophages from IFN-alpha/beta receptor knockout mice. Cotransfection of human Toll-like receptors 3 and 9 (receptors for dsRNA and CpG DNA, respectively) into 293T cells supported synergistic activation of an IL-8 promoter reporter construct by pIC, indicating interaction of the signaling pathways in driving the synergy response. In vivo stimulation of mice with pIC and CpG-ODN demonstrated synergy for serum IL-6 and IL-12p40 levels that correlated with an enhanced antitumor effect against established B16-F10 experimental pulmonary metastases. Treatment of tumor-bearing mice with pIC and CpG-ODN in combination resulted in enhanced nitric oxide synthase expression in lung tissue and enhanced up-regulation of class I major histocompatibility complex on splenic dendritic cells relative to treatments with either agent alone. In conclusion, the combined detection of viral pathogen-associated molecular patterns, i.e., dsRNA and CpG DNA, may mimic definitive viral recognition, resulting in an enhanced innate immune response that could be used for tumor vaccination or immunotherapy.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.CAN-04-0063</identifier><identifier>PMID: 15313929</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Animals ; Antineoplastic agents ; Biological and medical sciences ; Cell Line ; CpG Islands - immunology ; Dendritic Cells - immunology ; Dendritic Cells - metabolism ; DNA - immunology ; DNA-Binding Proteins - biosynthesis ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - immunology ; Enzyme Activation ; Humans ; Interferon Type I - immunology ; Interleukin-12 - biosynthesis ; Interleukin-12 - genetics ; Interleukin-12 - immunology ; Interleukin-6 - biosynthesis ; Interleukin-6 - genetics ; Interleukin-6 - immunology ; Interleukin-8 - biosynthesis ; Interleukin-8 - genetics ; Interleukin-8 - immunology ; Lung - metabolism ; Macrophage Activation - immunology ; Macrophages - immunology ; Macrophages - metabolism ; Macrophages - physiology ; Medical sciences ; Melanoma, Experimental - immunology ; Membrane Glycoproteins - biosynthesis ; Membrane Glycoproteins - genetics ; Membrane Glycoproteins - immunology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Nitric Oxide Synthase - biosynthesis ; Nitric Oxide Synthase - metabolism ; Nitric Oxide Synthase Type II ; Pharmacology. Drug treatments ; Poly I-C - pharmacology ; Promoter Regions, Genetic ; Receptors, Cell Surface - biosynthesis ; Receptors, Cell Surface - genetics ; Receptors, Cell Surface - immunology ; RNA, Double-Stranded - immunology ; Toll-Like Receptor 9 ; Toll-Like Receptors ; Transfection ; Tumor Necrosis Factor-alpha - biosynthesis ; Tumor Necrosis Factor-alpha - genetics ; Tumor Necrosis Factor-alpha - immunology ; Tumors</subject><ispartof>Cancer research (Chicago, Ill.), 2004-08, Vol.64 (16), p.5850-5860</ispartof><rights>2004 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c445t-8ff5f728d7910cd2d3f37af8b24e5e18ab93e301dce91506ff3827dae01fbc7d3</citedby><cites>FETCH-LOGICAL-c445t-8ff5f728d7910cd2d3f37af8b24e5e18ab93e301dce91506ff3827dae01fbc7d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,3356,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=16025457$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15313929$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>WHITMORE, Mark M</creatorcontrib><creatorcontrib>DEVEER, Michael J</creatorcontrib><creatorcontrib>EDLING, Andrea</creatorcontrib><creatorcontrib>OATES, Rhonda K</creatorcontrib><creatorcontrib>SIMONS, Brenna</creatorcontrib><creatorcontrib>LINDNER, Daniel</creatorcontrib><creatorcontrib>WILLIAMS, Bryan R. G</creatorcontrib><title>Synergistic activation of innate immunity by double-stranded RNA and CpG dna promotes enhanced antitumor activity</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>Double-stranded RNA (dsRNA) and unmethylated CpG sequences in DNA are pathogen-associated molecular patterns of viruses and bacteria that activate innate immunity. To examine whether dsRNA and CpG DNA could combine to provide enhanced stimulation of innate immune cells, murine macrophages were stimulated with poly-rI:rC (pIC), a dsRNA analog, and CpG-containing oligodeoxynucleotides (CpG-ODN). Combined treatments demonstrated synergy in nitric oxide, interleukin (IL)-12, tumor necrosis factor alpha, and IL-6 production. Studies using neutralizing antibodies for type I interferons (IFNs), IFN-alpha and IFN-beta, indicated that nitric oxide synthase synergism is mediated by paracrine/autocrine effects of IFN-beta. In contrast, enhanced cytokine production occurred independent of type I IFN and was maintained in macrophages from IFN-alpha/beta receptor knockout mice. Cotransfection of human Toll-like receptors 3 and 9 (receptors for dsRNA and CpG DNA, respectively) into 293T cells supported synergistic activation of an IL-8 promoter reporter construct by pIC, indicating interaction of the signaling pathways in driving the synergy response. In vivo stimulation of mice with pIC and CpG-ODN demonstrated synergy for serum IL-6 and IL-12p40 levels that correlated with an enhanced antitumor effect against established B16-F10 experimental pulmonary metastases. Treatment of tumor-bearing mice with pIC and CpG-ODN in combination resulted in enhanced nitric oxide synthase expression in lung tissue and enhanced up-regulation of class I major histocompatibility complex on splenic dendritic cells relative to treatments with either agent alone. In conclusion, the combined detection of viral pathogen-associated molecular patterns, i.e., dsRNA and CpG DNA, may mimic definitive viral recognition, resulting in an enhanced innate immune response that could be used for tumor vaccination or immunotherapy.</description><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Cell Line</subject><subject>CpG Islands - immunology</subject><subject>Dendritic Cells - immunology</subject><subject>Dendritic Cells - metabolism</subject><subject>DNA - immunology</subject><subject>DNA-Binding Proteins - biosynthesis</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - immunology</subject><subject>Enzyme Activation</subject><subject>Humans</subject><subject>Interferon Type I - immunology</subject><subject>Interleukin-12 - biosynthesis</subject><subject>Interleukin-12 - genetics</subject><subject>Interleukin-12 - immunology</subject><subject>Interleukin-6 - biosynthesis</subject><subject>Interleukin-6 - genetics</subject><subject>Interleukin-6 - immunology</subject><subject>Interleukin-8 - biosynthesis</subject><subject>Interleukin-8 - genetics</subject><subject>Interleukin-8 - immunology</subject><subject>Lung - metabolism</subject><subject>Macrophage Activation - immunology</subject><subject>Macrophages - immunology</subject><subject>Macrophages - metabolism</subject><subject>Macrophages - physiology</subject><subject>Medical sciences</subject><subject>Melanoma, Experimental - immunology</subject><subject>Membrane Glycoproteins - biosynthesis</subject><subject>Membrane Glycoproteins - genetics</subject><subject>Membrane Glycoproteins - immunology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Nitric Oxide Synthase - biosynthesis</subject><subject>Nitric Oxide Synthase - metabolism</subject><subject>Nitric Oxide Synthase Type II</subject><subject>Pharmacology. Drug treatments</subject><subject>Poly I-C - pharmacology</subject><subject>Promoter Regions, Genetic</subject><subject>Receptors, Cell Surface - biosynthesis</subject><subject>Receptors, Cell Surface - genetics</subject><subject>Receptors, Cell Surface - immunology</subject><subject>RNA, Double-Stranded - immunology</subject><subject>Toll-Like Receptor 9</subject><subject>Toll-Like Receptors</subject><subject>Transfection</subject><subject>Tumor Necrosis Factor-alpha - biosynthesis</subject><subject>Tumor Necrosis Factor-alpha - genetics</subject><subject>Tumor Necrosis Factor-alpha - immunology</subject><subject>Tumors</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUtLxDAUhYMoOj5-gpKN7qpJ0zTpchh8gSj4WIc0udFIm45NKsy_N8MMunSVG_juuYdzEDql5JJSLq8IIbLglSgvF_PHglQFITXbQTPKmSxEVfFdNPtlDtBhjJ_5yynh--ggQ5Q1ZTNDXy-rAOO7j8kbrE3y3zr5IeDBYR-CToB930_BpxVuV9gOU9tBEdOogwWLnx_nOE94sbzFNmi8HId-SBAxhA8dTCZ0SD5N_TBuxLPOMdpzuotwsn2P0NvN9evirnh4ur1fzB8Kk82nQjrHnSilFQ0lxpaWOSa0k21ZAQcqddswYIRaAw3lpHaOyVJYDYS61gjLjtDFRjeb-pogJtX7aKDrdIBhiqquhWwqIf4FqSQlbyTPIN-AZhxiHMGp5eh7Pa4UJWpdiloHrtaBq1yKIpVal5L3zrYHprYH-7e1bSED51tAR6M7l9M1Pv5xdTZQccF-AAmilvI</recordid><startdate>20040815</startdate><enddate>20040815</enddate><creator>WHITMORE, Mark M</creator><creator>DEVEER, Michael J</creator><creator>EDLING, Andrea</creator><creator>OATES, Rhonda K</creator><creator>SIMONS, Brenna</creator><creator>LINDNER, Daniel</creator><creator>WILLIAMS, Bryan R. 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G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c445t-8ff5f728d7910cd2d3f37af8b24e5e18ab93e301dce91506ff3827dae01fbc7d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>Cell Line</topic><topic>CpG Islands - immunology</topic><topic>Dendritic Cells - immunology</topic><topic>Dendritic Cells - metabolism</topic><topic>DNA - immunology</topic><topic>DNA-Binding Proteins - biosynthesis</topic><topic>DNA-Binding Proteins - genetics</topic><topic>DNA-Binding Proteins - immunology</topic><topic>Enzyme Activation</topic><topic>Humans</topic><topic>Interferon Type I - immunology</topic><topic>Interleukin-12 - biosynthesis</topic><topic>Interleukin-12 - genetics</topic><topic>Interleukin-12 - immunology</topic><topic>Interleukin-6 - biosynthesis</topic><topic>Interleukin-6 - genetics</topic><topic>Interleukin-6 - immunology</topic><topic>Interleukin-8 - biosynthesis</topic><topic>Interleukin-8 - genetics</topic><topic>Interleukin-8 - immunology</topic><topic>Lung - metabolism</topic><topic>Macrophage Activation - immunology</topic><topic>Macrophages - immunology</topic><topic>Macrophages - metabolism</topic><topic>Macrophages - physiology</topic><topic>Medical sciences</topic><topic>Melanoma, Experimental - immunology</topic><topic>Membrane Glycoproteins - biosynthesis</topic><topic>Membrane Glycoproteins - genetics</topic><topic>Membrane Glycoproteins - immunology</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Nitric Oxide Synthase - biosynthesis</topic><topic>Nitric Oxide Synthase - metabolism</topic><topic>Nitric Oxide Synthase Type II</topic><topic>Pharmacology. Drug treatments</topic><topic>Poly I-C - pharmacology</topic><topic>Promoter Regions, Genetic</topic><topic>Receptors, Cell Surface - biosynthesis</topic><topic>Receptors, Cell Surface - genetics</topic><topic>Receptors, Cell Surface - immunology</topic><topic>RNA, Double-Stranded - immunology</topic><topic>Toll-Like Receptor 9</topic><topic>Toll-Like Receptors</topic><topic>Transfection</topic><topic>Tumor Necrosis Factor-alpha - biosynthesis</topic><topic>Tumor Necrosis Factor-alpha - genetics</topic><topic>Tumor Necrosis Factor-alpha - immunology</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>WHITMORE, Mark M</creatorcontrib><creatorcontrib>DEVEER, Michael J</creatorcontrib><creatorcontrib>EDLING, Andrea</creatorcontrib><creatorcontrib>OATES, Rhonda K</creatorcontrib><creatorcontrib>SIMONS, Brenna</creatorcontrib><creatorcontrib>LINDNER, Daniel</creatorcontrib><creatorcontrib>WILLIAMS, Bryan R. 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G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synergistic activation of innate immunity by double-stranded RNA and CpG dna promotes enhanced antitumor activity</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2004-08-15</date><risdate>2004</risdate><volume>64</volume><issue>16</issue><spage>5850</spage><epage>5860</epage><pages>5850-5860</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><abstract>Double-stranded RNA (dsRNA) and unmethylated CpG sequences in DNA are pathogen-associated molecular patterns of viruses and bacteria that activate innate immunity. To examine whether dsRNA and CpG DNA could combine to provide enhanced stimulation of innate immune cells, murine macrophages were stimulated with poly-rI:rC (pIC), a dsRNA analog, and CpG-containing oligodeoxynucleotides (CpG-ODN). Combined treatments demonstrated synergy in nitric oxide, interleukin (IL)-12, tumor necrosis factor alpha, and IL-6 production. Studies using neutralizing antibodies for type I interferons (IFNs), IFN-alpha and IFN-beta, indicated that nitric oxide synthase synergism is mediated by paracrine/autocrine effects of IFN-beta. In contrast, enhanced cytokine production occurred independent of type I IFN and was maintained in macrophages from IFN-alpha/beta receptor knockout mice. Cotransfection of human Toll-like receptors 3 and 9 (receptors for dsRNA and CpG DNA, respectively) into 293T cells supported synergistic activation of an IL-8 promoter reporter construct by pIC, indicating interaction of the signaling pathways in driving the synergy response. In vivo stimulation of mice with pIC and CpG-ODN demonstrated synergy for serum IL-6 and IL-12p40 levels that correlated with an enhanced antitumor effect against established B16-F10 experimental pulmonary metastases. Treatment of tumor-bearing mice with pIC and CpG-ODN in combination resulted in enhanced nitric oxide synthase expression in lung tissue and enhanced up-regulation of class I major histocompatibility complex on splenic dendritic cells relative to treatments with either agent alone. In conclusion, the combined detection of viral pathogen-associated molecular patterns, i.e., dsRNA and CpG DNA, may mimic definitive viral recognition, resulting in an enhanced innate immune response that could be used for tumor vaccination or immunotherapy.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>15313929</pmid><doi>10.1158/0008-5472.CAN-04-0063</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Antineoplastic agents Biological and medical sciences Cell Line CpG Islands - immunology Dendritic Cells - immunology Dendritic Cells - metabolism DNA - immunology DNA-Binding Proteins - biosynthesis DNA-Binding Proteins - genetics DNA-Binding Proteins - immunology Enzyme Activation Humans Interferon Type I - immunology Interleukin-12 - biosynthesis Interleukin-12 - genetics Interleukin-12 - immunology Interleukin-6 - biosynthesis Interleukin-6 - genetics Interleukin-6 - immunology Interleukin-8 - biosynthesis Interleukin-8 - genetics Interleukin-8 - immunology Lung - metabolism Macrophage Activation - immunology Macrophages - immunology Macrophages - metabolism Macrophages - physiology Medical sciences Melanoma, Experimental - immunology Membrane Glycoproteins - biosynthesis Membrane Glycoproteins - genetics Membrane Glycoproteins - immunology Mice Mice, Inbred C57BL Mice, Knockout Nitric Oxide Synthase - biosynthesis Nitric Oxide Synthase - metabolism Nitric Oxide Synthase Type II Pharmacology. Drug treatments Poly I-C - pharmacology Promoter Regions, Genetic Receptors, Cell Surface - biosynthesis Receptors, Cell Surface - genetics Receptors, Cell Surface - immunology RNA, Double-Stranded - immunology Toll-Like Receptor 9 Toll-Like Receptors Transfection Tumor Necrosis Factor-alpha - biosynthesis Tumor Necrosis Factor-alpha - genetics Tumor Necrosis Factor-alpha - immunology Tumors |
title | Synergistic activation of innate immunity by double-stranded RNA and CpG dna promotes enhanced antitumor activity |
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