Poly(I:C) Drives Type I IFN- and TGFβ-Mediated Inflammation and Dermal Fibrosis Simulating Altered Gene Expression in Systemic Sclerosis
Immune activation of fibrosis likely has a crucial role in the pathogenesis of systemic sclerosis (SSc). The aim of this study was to better understand the innate immune regulation and associated IFN- and transforming growth factor-β (TGFβ)-responsive gene expression in SSc skin and dermal fibroblas...
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| Veröffentlicht in: | Journal of investigative dermatology 2010-11, Vol.130 (11), p.2583-2593 |
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| creator | Farina, Giuseppina A. York, Michael R. Di Marzio, Michael Collins, Cindy A. Meller, Stephan Homey, Bernhard Rifkin, Ian R. Marshak-Rothstein, Ann Radstake, Timothy R.D.J. Lafyatis, Robert |
| description | Immune activation of fibrosis likely has a crucial role in the pathogenesis of systemic sclerosis (SSc). The aim of this study was to better understand the innate immune regulation and associated IFN- and transforming growth factor-β (TGFβ)-responsive gene expression in SSc skin and dermal fibroblasts, in particular the effect of different Toll-like receptor (TLR) ligands. To better understand the relationship between inflammation and fibrosis in vivo, we developed a murine model for chronic innate immune stimulation. We found that expression of both IFN- and TGFβ-responsive genes is increased in SSc skin and SSc fibroblasts when stimulated by TLR ligands. In contrast, cutaneous lupus skin showed much more highly upregulated IFN-responsive and much less highly upregulated TGFβ-responsive gene expression. Of the TLRs ligands tested, the TLR3 ligand, polyinosinic/polycytidylic acid (Poly(I:C)), most highly increased fibroblast expression of both IFN- and TGFβ-responsive genes as well as TLR3. Chronic subcutaneous immune stimulation by Poly(I:C) stimulated inflammation, and IFN- and TGFβ-responsive gene expression. However, in this model, type I IFNs had no apparent role in regulating TGFβ activity in the skin. These results suggest that TLR agonists may be important stimuli of dermal fibrosis, which is potentially mediated by TLR3 or other innate immune receptors. |
| doi_str_mv | 10.1038/jid.2010.200 |
| format | Article |
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The aim of this study was to better understand the innate immune regulation and associated IFN- and transforming growth factor-β (TGFβ)-responsive gene expression in SSc skin and dermal fibroblasts, in particular the effect of different Toll-like receptor (TLR) ligands. To better understand the relationship between inflammation and fibrosis in vivo, we developed a murine model for chronic innate immune stimulation. We found that expression of both IFN- and TGFβ-responsive genes is increased in SSc skin and SSc fibroblasts when stimulated by TLR ligands. In contrast, cutaneous lupus skin showed much more highly upregulated IFN-responsive and much less highly upregulated TGFβ-responsive gene expression. Of the TLRs ligands tested, the TLR3 ligand, polyinosinic/polycytidylic acid (Poly(I:C)), most highly increased fibroblast expression of both IFN- and TGFβ-responsive genes as well as TLR3. Chronic subcutaneous immune stimulation by Poly(I:C) stimulated inflammation, and IFN- and TGFβ-responsive gene expression. However, in this model, type I IFNs had no apparent role in regulating TGFβ activity in the skin. These results suggest that TLR agonists may be important stimuli of dermal fibrosis, which is potentially mediated by TLR3 or other innate immune receptors.</description><identifier>ISSN: 0022-202X</identifier><identifier>EISSN: 1523-1747</identifier><identifier>DOI: 10.1038/jid.2010.200</identifier><identifier>PMID: 20613770</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adaptor Proteins, Vesicular Transport - genetics ; Adaptor Proteins, Vesicular Transport - metabolism ; Animals ; Cells, Cultured ; Dermatitis - genetics ; Dermatitis - immunology ; Dermatitis - pathology ; Dermis - immunology ; Dermis - pathology ; Disease Models, Animal ; Fibroblasts - cytology ; Fibroblasts - drug effects ; Fibroblasts - immunology ; Gene Expression - immunology ; GTP-Binding Proteins - metabolism ; Humans ; Interferon Type I - immunology ; Interferon Type I - metabolism ; Interferon-gamma - immunology ; Interferon-gamma - metabolism ; Lupus Erythematosus, Cutaneous - genetics ; Lupus Erythematosus, Cutaneous - immunology ; Lupus Erythematosus, Cutaneous - pathology ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Myxovirus Resistance Proteins ; Poly I-C - metabolism ; Poly I-C - pharmacology ; Scleroderma, Systemic - genetics ; Scleroderma, Systemic - immunology ; Scleroderma, Systemic - pathology ; Toll-Like Receptor 3 - agonists ; Toll-Like Receptor 3 - immunology ; Toll-Like Receptor 3 - metabolism ; Transforming Growth Factor beta - immunology ; Transforming Growth Factor beta - metabolism</subject><ispartof>Journal of investigative dermatology, 2010-11, Vol.130 (11), p.2583-2593</ispartof><rights>2010 The Society for Investigative Dermatology, Inc</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c487t-65b09824ed5e304a86d29965308479ecce3d09d28de4200fd068a0cac5f3e2523</citedby><cites>FETCH-LOGICAL-c487t-65b09824ed5e304a86d29965308479ecce3d09d28de4200fd068a0cac5f3e2523</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,781,785,886,27929,27930,64392</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20613770$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Farina, Giuseppina A.</creatorcontrib><creatorcontrib>York, Michael R.</creatorcontrib><creatorcontrib>Di Marzio, Michael</creatorcontrib><creatorcontrib>Collins, Cindy A.</creatorcontrib><creatorcontrib>Meller, Stephan</creatorcontrib><creatorcontrib>Homey, Bernhard</creatorcontrib><creatorcontrib>Rifkin, Ian R.</creatorcontrib><creatorcontrib>Marshak-Rothstein, Ann</creatorcontrib><creatorcontrib>Radstake, Timothy R.D.J.</creatorcontrib><creatorcontrib>Lafyatis, Robert</creatorcontrib><title>Poly(I:C) Drives Type I IFN- and TGFβ-Mediated Inflammation and Dermal Fibrosis Simulating Altered Gene Expression in Systemic Sclerosis</title><title>Journal of investigative dermatology</title><addtitle>J Invest Dermatol</addtitle><description>Immune activation of fibrosis likely has a crucial role in the pathogenesis of systemic sclerosis (SSc). The aim of this study was to better understand the innate immune regulation and associated IFN- and transforming growth factor-β (TGFβ)-responsive gene expression in SSc skin and dermal fibroblasts, in particular the effect of different Toll-like receptor (TLR) ligands. To better understand the relationship between inflammation and fibrosis in vivo, we developed a murine model for chronic innate immune stimulation. We found that expression of both IFN- and TGFβ-responsive genes is increased in SSc skin and SSc fibroblasts when stimulated by TLR ligands. In contrast, cutaneous lupus skin showed much more highly upregulated IFN-responsive and much less highly upregulated TGFβ-responsive gene expression. Of the TLRs ligands tested, the TLR3 ligand, polyinosinic/polycytidylic acid (Poly(I:C)), most highly increased fibroblast expression of both IFN- and TGFβ-responsive genes as well as TLR3. Chronic subcutaneous immune stimulation by Poly(I:C) stimulated inflammation, and IFN- and TGFβ-responsive gene expression. However, in this model, type I IFNs had no apparent role in regulating TGFβ activity in the skin. These results suggest that TLR agonists may be important stimuli of dermal fibrosis, which is potentially mediated by TLR3 or other innate immune receptors.</description><subject>Adaptor Proteins, Vesicular Transport - genetics</subject><subject>Adaptor Proteins, Vesicular Transport - metabolism</subject><subject>Animals</subject><subject>Cells, Cultured</subject><subject>Dermatitis - genetics</subject><subject>Dermatitis - immunology</subject><subject>Dermatitis - pathology</subject><subject>Dermis - immunology</subject><subject>Dermis - pathology</subject><subject>Disease Models, Animal</subject><subject>Fibroblasts - cytology</subject><subject>Fibroblasts - drug effects</subject><subject>Fibroblasts - immunology</subject><subject>Gene Expression - immunology</subject><subject>GTP-Binding Proteins - metabolism</subject><subject>Humans</subject><subject>Interferon Type I - immunology</subject><subject>Interferon Type I - metabolism</subject><subject>Interferon-gamma - immunology</subject><subject>Interferon-gamma - metabolism</subject><subject>Lupus Erythematosus, Cutaneous - genetics</subject><subject>Lupus Erythematosus, Cutaneous - immunology</subject><subject>Lupus Erythematosus, Cutaneous - pathology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Mutant Strains</subject><subject>Myxovirus Resistance Proteins</subject><subject>Poly I-C - metabolism</subject><subject>Poly I-C - pharmacology</subject><subject>Scleroderma, Systemic - genetics</subject><subject>Scleroderma, Systemic - immunology</subject><subject>Scleroderma, Systemic - pathology</subject><subject>Toll-Like Receptor 3 - agonists</subject><subject>Toll-Like Receptor 3 - immunology</subject><subject>Toll-Like Receptor 3 - metabolism</subject><subject>Transforming Growth Factor beta - immunology</subject><subject>Transforming Growth Factor beta - metabolism</subject><issn>0022-202X</issn><issn>1523-1747</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkd9u0zAUxiMEYt3gjmvkO0Ai48SJE2cXSFO3lkjjj9QicWe59snw5DjFTqv1EXgdHoRnwl1GBRISN7as8zvfOf6-JHmWwWkGOX9zY_QphfiiAA-SScZonmZVUT1MJgCUphTol6PkOIQbgKwsGH-cHFEos7yqYJJ8_9Tb3cvmbPqKXHizxUCWuzWShjSzDymRTpPlfPbzR_oetZEDatK41squk4Pp3V39An0nLZmZle-DCWRhuo2NZXdNzu2APvbM0SG5vF17DGHfZhxZ7MKAnVFkoSzeNT5JHrXSBnx6f58kn2eXy-m79OrjvJmeX6Wq4NWQlmwFNacFaoY5FJKXmtZ1yXLgRVWjUphrqDXlGovoSKuh5BKUVKzNkUZzTpK3o-56s-pQK3SDl1asvemk34leGvF3xZmv4rrfijihZIxHgRf3Ar7_tsEwiM4EhdZKh_0miLrkGeN1lf2XrBjnOcsLFsnXI6miF8Fje9gnA7GPWcSYxT7meEDEn__5hwP8O9cIkBFwcth4PABRZS8yapQjgtHsrUEvgjLoVAzaoxqE7s2_h_8CUlfBmw</recordid><startdate>20101101</startdate><enddate>20101101</enddate><creator>Farina, Giuseppina A.</creator><creator>York, Michael R.</creator><creator>Di Marzio, Michael</creator><creator>Collins, Cindy A.</creator><creator>Meller, Stephan</creator><creator>Homey, Bernhard</creator><creator>Rifkin, Ian R.</creator><creator>Marshak-Rothstein, Ann</creator><creator>Radstake, Timothy R.D.J.</creator><creator>Lafyatis, Robert</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><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>7X8</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20101101</creationdate><title>Poly(I:C) Drives Type I IFN- and TGFβ-Mediated Inflammation and Dermal Fibrosis Simulating Altered Gene Expression in Systemic Sclerosis</title><author>Farina, Giuseppina A. ; York, Michael R. ; Di Marzio, Michael ; Collins, Cindy A. ; Meller, Stephan ; Homey, Bernhard ; Rifkin, Ian R. ; Marshak-Rothstein, Ann ; Radstake, Timothy R.D.J. ; Lafyatis, Robert</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c487t-65b09824ed5e304a86d29965308479ecce3d09d28de4200fd068a0cac5f3e2523</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Adaptor Proteins, Vesicular Transport - genetics</topic><topic>Adaptor Proteins, Vesicular Transport - metabolism</topic><topic>Animals</topic><topic>Cells, Cultured</topic><topic>Dermatitis - genetics</topic><topic>Dermatitis - immunology</topic><topic>Dermatitis - pathology</topic><topic>Dermis - immunology</topic><topic>Dermis - pathology</topic><topic>Disease Models, Animal</topic><topic>Fibroblasts - cytology</topic><topic>Fibroblasts - drug effects</topic><topic>Fibroblasts - immunology</topic><topic>Gene Expression - immunology</topic><topic>GTP-Binding Proteins - metabolism</topic><topic>Humans</topic><topic>Interferon Type I - immunology</topic><topic>Interferon Type I - metabolism</topic><topic>Interferon-gamma - immunology</topic><topic>Interferon-gamma - metabolism</topic><topic>Lupus Erythematosus, Cutaneous - genetics</topic><topic>Lupus Erythematosus, Cutaneous - immunology</topic><topic>Lupus Erythematosus, Cutaneous - pathology</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Mutant Strains</topic><topic>Myxovirus Resistance Proteins</topic><topic>Poly I-C - metabolism</topic><topic>Poly I-C - pharmacology</topic><topic>Scleroderma, Systemic - genetics</topic><topic>Scleroderma, Systemic - immunology</topic><topic>Scleroderma, Systemic - pathology</topic><topic>Toll-Like Receptor 3 - agonists</topic><topic>Toll-Like Receptor 3 - immunology</topic><topic>Toll-Like Receptor 3 - metabolism</topic><topic>Transforming Growth Factor beta - immunology</topic><topic>Transforming Growth Factor beta - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Farina, Giuseppina A.</creatorcontrib><creatorcontrib>York, Michael R.</creatorcontrib><creatorcontrib>Di Marzio, Michael</creatorcontrib><creatorcontrib>Collins, Cindy A.</creatorcontrib><creatorcontrib>Meller, Stephan</creatorcontrib><creatorcontrib>Homey, Bernhard</creatorcontrib><creatorcontrib>Rifkin, Ian R.</creatorcontrib><creatorcontrib>Marshak-Rothstein, Ann</creatorcontrib><creatorcontrib>Radstake, Timothy R.D.J.</creatorcontrib><creatorcontrib>Lafyatis, Robert</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of investigative dermatology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Farina, Giuseppina A.</au><au>York, Michael R.</au><au>Di Marzio, Michael</au><au>Collins, Cindy A.</au><au>Meller, Stephan</au><au>Homey, Bernhard</au><au>Rifkin, Ian R.</au><au>Marshak-Rothstein, Ann</au><au>Radstake, Timothy R.D.J.</au><au>Lafyatis, Robert</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Poly(I:C) Drives Type I IFN- and TGFβ-Mediated Inflammation and Dermal Fibrosis Simulating Altered Gene Expression in Systemic Sclerosis</atitle><jtitle>Journal of investigative dermatology</jtitle><addtitle>J Invest Dermatol</addtitle><date>2010-11-01</date><risdate>2010</risdate><volume>130</volume><issue>11</issue><spage>2583</spage><epage>2593</epage><pages>2583-2593</pages><issn>0022-202X</issn><eissn>1523-1747</eissn><abstract>Immune activation of fibrosis likely has a crucial role in the pathogenesis of systemic sclerosis (SSc). The aim of this study was to better understand the innate immune regulation and associated IFN- and transforming growth factor-β (TGFβ)-responsive gene expression in SSc skin and dermal fibroblasts, in particular the effect of different Toll-like receptor (TLR) ligands. To better understand the relationship between inflammation and fibrosis in vivo, we developed a murine model for chronic innate immune stimulation. We found that expression of both IFN- and TGFβ-responsive genes is increased in SSc skin and SSc fibroblasts when stimulated by TLR ligands. In contrast, cutaneous lupus skin showed much more highly upregulated IFN-responsive and much less highly upregulated TGFβ-responsive gene expression. Of the TLRs ligands tested, the TLR3 ligand, polyinosinic/polycytidylic acid (Poly(I:C)), most highly increased fibroblast expression of both IFN- and TGFβ-responsive genes as well as TLR3. Chronic subcutaneous immune stimulation by Poly(I:C) stimulated inflammation, and IFN- and TGFβ-responsive gene expression. However, in this model, type I IFNs had no apparent role in regulating TGFβ activity in the skin. These results suggest that TLR agonists may be important stimuli of dermal fibrosis, which is potentially mediated by TLR3 or other innate immune receptors.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>20613770</pmid><doi>10.1038/jid.2010.200</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adaptor Proteins, Vesicular Transport - genetics Adaptor Proteins, Vesicular Transport - metabolism Animals Cells, Cultured Dermatitis - genetics Dermatitis - immunology Dermatitis - pathology Dermis - immunology Dermis - pathology Disease Models, Animal Fibroblasts - cytology Fibroblasts - drug effects Fibroblasts - immunology Gene Expression - immunology GTP-Binding Proteins - metabolism Humans Interferon Type I - immunology Interferon Type I - metabolism Interferon-gamma - immunology Interferon-gamma - metabolism Lupus Erythematosus, Cutaneous - genetics Lupus Erythematosus, Cutaneous - immunology Lupus Erythematosus, Cutaneous - pathology Mice Mice, Inbred C57BL Mice, Mutant Strains Myxovirus Resistance Proteins Poly I-C - metabolism Poly I-C - pharmacology Scleroderma, Systemic - genetics Scleroderma, Systemic - immunology Scleroderma, Systemic - pathology Toll-Like Receptor 3 - agonists Toll-Like Receptor 3 - immunology Toll-Like Receptor 3 - metabolism Transforming Growth Factor beta - immunology Transforming Growth Factor beta - metabolism |
| title | Poly(I:C) Drives Type I IFN- and TGFβ-Mediated Inflammation and Dermal Fibrosis Simulating Altered Gene Expression in Systemic Sclerosis |
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