Transcriptomic analysis of pathways regulated by toll-like receptor 4 in a murine model of chronic pulmonary inflammation and carcinogenesis
<p>Abstract</p> <p>Background</p> <p>Therapeutic strategies exist for human pulmonary neoplasia, however due to the heterogeneity of the disease, most are not very effective. The innate immunity gene, toll-like receptor 4 (TLR4), protects against chronic pulmonary infla...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2009-11-01
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| Series: | Molecular Cancer |
| Online Access: | http://www.molecular-cancer.com/content/8/1/107 |
| _version_ | 1818445358004436992 |
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| author | Grissom Sherry F Walker Christopher Rondini Elizabeth A Degraff Laura M Fostel Jennifer Bauer Alison K Foley Julie Kleeberger Steven R |
| author_facet | Grissom Sherry F Walker Christopher Rondini Elizabeth A Degraff Laura M Fostel Jennifer Bauer Alison K Foley Julie Kleeberger Steven R |
| author_sort | Grissom Sherry F |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Therapeutic strategies exist for human pulmonary neoplasia, however due to the heterogeneity of the disease, most are not very effective. The innate immunity gene, toll-like receptor 4 (TLR4), protects against chronic pulmonary inflammation and tumorigenesis in mice, but the mechanism is unclear. This study was designed to identify TLR4-mediated gene expression pathways that may be used as prognostic indicators of susceptibility to lung tumorigenesis in mice and provide insight into the mechanism.</p> <p>Methods</p> <p>Whole lung mRNA was isolated from C.C3H-<it>Tlr4</it><sup><it>Lps</it>-<it>d </it></sup>(BALB<sup><it>Lps</it>-<it>d</it></sup>; <it>Tlr4 </it>mutant) and BALB/c (<it>Tlr4 </it>normal) mice following butylated hydroxytoluene (BHT)-treatment (four weekly ip. injections; 150-200 mg/kg/each; "promotion"). mRNA from micro-dissected tumors (adenomas) and adjacent uninvolved tissue from both strains were also compared 27 wks after a single carcinogen injection (3-methylcholanthrene (MCA), 10 μg/g; "control") or followed by BHT (6 weekly ip. injections; 125-200 mg/kg/each; "progression"). Bronchoalveolar lavage fluid was analyzed for inflammatory cell content and total protein determination, a marker of lung hyperpermeability; inflammation was also assessed using immunohistochemical staining for macrophages (F4/80) and lymphocytes (CD3) in mice bearing tumors (progression).</p> <p>Results</p> <p>During promotion, the majority of genes identified in the BALB<sup><it>Lps</it>-<it>d </it></sup>compared to BALB/c mice (P < 0.05) were involved in epithelial growth factor receptor (EGFR) signaling (e.g. epiregulin (<it>Ereg</it>)), secreted phosphoprotein 1(<it>Spp1</it>)), which can lead to cell growth and eventual tumor development. Inflammation was significantly higher in BALB<sup><it>Lps</it>-<it>d </it></sup>compared to BALB/c mice during progression, similar to the observed response during tumor promotion in these strains. Increases in genes involved in signaling through the EGFR pathway (e.g. <it>Ereg</it>, <it>Spp1</it>) were also observed during progression in addition to continued inflammation, chemotactic, and immune response gene expression in the BALB<sup><it>Lps</it>-<it>d </it></sup>versus BALB/c mice (<it>P </it>< 0.05), which appears to provide more favorable conditions for cell growth and tumor development. In support of these findings, the BALB/c mice also had significantly reduced expression of many immune response and inflammatory genes in both the tumors and uninvolved tissue.</p> <p>Conclusion</p> <p>This transcriptomic study determined the protective effect of TLR4 in lung carcinogenesis inhibition of multiple pathways including EGFR (e.g. <it>Ereg</it>), inflammatory response genes (e.g. <it>Cxcl5)</it>, chemotaxis (e.g. <it>Ccr1</it>) and other cell proliferation genes (e.g. <it>Arg1</it>, <it>Pthlh</it>). Future studies will determine the utility of these pathways as indicators of immune system deficiencies and tumorigenesis.</p> |
| first_indexed | 2024-12-14T19:30:33Z |
| format | Article |
| id | doaj.art-2bf0430eba0348b6b2c277b6e0afbb5c |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-12-14T19:30:33Z |
| publishDate | 2009-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-2bf0430eba0348b6b2c277b6e0afbb5c2022-12-21T22:50:05ZengBMCMolecular Cancer1476-45982009-11-018110710.1186/1476-4598-8-107Transcriptomic analysis of pathways regulated by toll-like receptor 4 in a murine model of chronic pulmonary inflammation and carcinogenesisGrissom Sherry FWalker ChristopherRondini Elizabeth ADegraff Laura MFostel JenniferBauer Alison KFoley JulieKleeberger Steven R<p>Abstract</p> <p>Background</p> <p>Therapeutic strategies exist for human pulmonary neoplasia, however due to the heterogeneity of the disease, most are not very effective. The innate immunity gene, toll-like receptor 4 (TLR4), protects against chronic pulmonary inflammation and tumorigenesis in mice, but the mechanism is unclear. This study was designed to identify TLR4-mediated gene expression pathways that may be used as prognostic indicators of susceptibility to lung tumorigenesis in mice and provide insight into the mechanism.</p> <p>Methods</p> <p>Whole lung mRNA was isolated from C.C3H-<it>Tlr4</it><sup><it>Lps</it>-<it>d </it></sup>(BALB<sup><it>Lps</it>-<it>d</it></sup>; <it>Tlr4 </it>mutant) and BALB/c (<it>Tlr4 </it>normal) mice following butylated hydroxytoluene (BHT)-treatment (four weekly ip. injections; 150-200 mg/kg/each; "promotion"). mRNA from micro-dissected tumors (adenomas) and adjacent uninvolved tissue from both strains were also compared 27 wks after a single carcinogen injection (3-methylcholanthrene (MCA), 10 μg/g; "control") or followed by BHT (6 weekly ip. injections; 125-200 mg/kg/each; "progression"). Bronchoalveolar lavage fluid was analyzed for inflammatory cell content and total protein determination, a marker of lung hyperpermeability; inflammation was also assessed using immunohistochemical staining for macrophages (F4/80) and lymphocytes (CD3) in mice bearing tumors (progression).</p> <p>Results</p> <p>During promotion, the majority of genes identified in the BALB<sup><it>Lps</it>-<it>d </it></sup>compared to BALB/c mice (P < 0.05) were involved in epithelial growth factor receptor (EGFR) signaling (e.g. epiregulin (<it>Ereg</it>)), secreted phosphoprotein 1(<it>Spp1</it>)), which can lead to cell growth and eventual tumor development. Inflammation was significantly higher in BALB<sup><it>Lps</it>-<it>d </it></sup>compared to BALB/c mice during progression, similar to the observed response during tumor promotion in these strains. Increases in genes involved in signaling through the EGFR pathway (e.g. <it>Ereg</it>, <it>Spp1</it>) were also observed during progression in addition to continued inflammation, chemotactic, and immune response gene expression in the BALB<sup><it>Lps</it>-<it>d </it></sup>versus BALB/c mice (<it>P </it>< 0.05), which appears to provide more favorable conditions for cell growth and tumor development. In support of these findings, the BALB/c mice also had significantly reduced expression of many immune response and inflammatory genes in both the tumors and uninvolved tissue.</p> <p>Conclusion</p> <p>This transcriptomic study determined the protective effect of TLR4 in lung carcinogenesis inhibition of multiple pathways including EGFR (e.g. <it>Ereg</it>), inflammatory response genes (e.g. <it>Cxcl5)</it>, chemotaxis (e.g. <it>Ccr1</it>) and other cell proliferation genes (e.g. <it>Arg1</it>, <it>Pthlh</it>). Future studies will determine the utility of these pathways as indicators of immune system deficiencies and tumorigenesis.</p>http://www.molecular-cancer.com/content/8/1/107 |
| spellingShingle | Grissom Sherry F Walker Christopher Rondini Elizabeth A Degraff Laura M Fostel Jennifer Bauer Alison K Foley Julie Kleeberger Steven R Transcriptomic analysis of pathways regulated by toll-like receptor 4 in a murine model of chronic pulmonary inflammation and carcinogenesis Molecular Cancer |
| title | Transcriptomic analysis of pathways regulated by toll-like receptor 4 in a murine model of chronic pulmonary inflammation and carcinogenesis |
| title_full | Transcriptomic analysis of pathways regulated by toll-like receptor 4 in a murine model of chronic pulmonary inflammation and carcinogenesis |
| title_fullStr | Transcriptomic analysis of pathways regulated by toll-like receptor 4 in a murine model of chronic pulmonary inflammation and carcinogenesis |
| title_full_unstemmed | Transcriptomic analysis of pathways regulated by toll-like receptor 4 in a murine model of chronic pulmonary inflammation and carcinogenesis |
| title_short | Transcriptomic analysis of pathways regulated by toll-like receptor 4 in a murine model of chronic pulmonary inflammation and carcinogenesis |
| title_sort | transcriptomic analysis of pathways regulated by toll like receptor 4 in a murine model of chronic pulmonary inflammation and carcinogenesis |
| url | http://www.molecular-cancer.com/content/8/1/107 |
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