Immunomodulatory effects of etanercept in a model of brain injury act through attenuation of the acute-phase response.
TNF-alpha has proved to be a successful target in the treatment of many peripheral inflammatory diseases, but the same interventions worsen immune-mediated CNS disease. However, anti-TNF-alpha strategies may offer promise as therapy for non-immune CNS injury. In this study, we have microinjected IL-...
| Main Authors: | , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2007
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| _version_ | 1797058950729826304 |
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| author | Campbell, S Jiang, Y Davis, A Farrands, R Holbrook, J Leppert, D Anthony, D |
| author_facet | Campbell, S Jiang, Y Davis, A Farrands, R Holbrook, J Leppert, D Anthony, D |
| author_sort | Campbell, S |
| collection | OXFORD |
| description | TNF-alpha has proved to be a successful target in the treatment of many peripheral inflammatory diseases, but the same interventions worsen immune-mediated CNS disease. However, anti-TNF-alpha strategies may offer promise as therapy for non-immune CNS injury. In this study, we have microinjected IL-1beta or lipopolysaccharide (LPS) into the rat brain as a simple model of brain injury and have systemically administered the TNF-alpha antagonist etanercept to discover whether hepatic TNF-alpha, produced as part of the acute-phase response to CNS injury, modulates the inflammatory response in the brain. We report a significant reduction in neutrophil numbers recruited to the IL-1beta- or LPS-challenged brain as a result of TNF-alpha inhibition. We also show an attenuation in the levels of hepatic mRNA including TNF-alpha mRNA and of TNF-alpha-induced genes, such as the chemokines CCL-2, CXCL-5, and CXCL-10, although other chemokines elevated by the injury were not significantly changed. The reduction in hepatic chemokine synthesis results in reduced numbers of circulating neutrophils, and also a reduction in the numbers recruited to the liver as a consequence of brain injury. These findings suggest that TNF-alpha inhibitors may reduce CNS inflammatory responses by targeting the hepatic acute-phase response, and thus therapies for brain injury need not cross the blood-brain barrier to be effective. |
| first_indexed | 2024-03-06T19:57:19Z |
| format | Journal article |
| id | oxford-uuid:2610a9c9-d79e-4942-8e46-ca6f958241b7 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T19:57:19Z |
| publishDate | 2007 |
| record_format | dspace |
| spelling | oxford-uuid:2610a9c9-d79e-4942-8e46-ca6f958241b72022-03-26T11:58:54ZImmunomodulatory effects of etanercept in a model of brain injury act through attenuation of the acute-phase response.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:2610a9c9-d79e-4942-8e46-ca6f958241b7EnglishSymplectic Elements at Oxford2007Campbell, SJiang, YDavis, AFarrands, RHolbrook, JLeppert, DAnthony, DTNF-alpha has proved to be a successful target in the treatment of many peripheral inflammatory diseases, but the same interventions worsen immune-mediated CNS disease. However, anti-TNF-alpha strategies may offer promise as therapy for non-immune CNS injury. In this study, we have microinjected IL-1beta or lipopolysaccharide (LPS) into the rat brain as a simple model of brain injury and have systemically administered the TNF-alpha antagonist etanercept to discover whether hepatic TNF-alpha, produced as part of the acute-phase response to CNS injury, modulates the inflammatory response in the brain. We report a significant reduction in neutrophil numbers recruited to the IL-1beta- or LPS-challenged brain as a result of TNF-alpha inhibition. We also show an attenuation in the levels of hepatic mRNA including TNF-alpha mRNA and of TNF-alpha-induced genes, such as the chemokines CCL-2, CXCL-5, and CXCL-10, although other chemokines elevated by the injury were not significantly changed. The reduction in hepatic chemokine synthesis results in reduced numbers of circulating neutrophils, and also a reduction in the numbers recruited to the liver as a consequence of brain injury. These findings suggest that TNF-alpha inhibitors may reduce CNS inflammatory responses by targeting the hepatic acute-phase response, and thus therapies for brain injury need not cross the blood-brain barrier to be effective. |
| spellingShingle | Campbell, S Jiang, Y Davis, A Farrands, R Holbrook, J Leppert, D Anthony, D Immunomodulatory effects of etanercept in a model of brain injury act through attenuation of the acute-phase response. |
| title | Immunomodulatory effects of etanercept in a model of brain injury act through attenuation of the acute-phase response. |
| title_full | Immunomodulatory effects of etanercept in a model of brain injury act through attenuation of the acute-phase response. |
| title_fullStr | Immunomodulatory effects of etanercept in a model of brain injury act through attenuation of the acute-phase response. |
| title_full_unstemmed | Immunomodulatory effects of etanercept in a model of brain injury act through attenuation of the acute-phase response. |
| title_short | Immunomodulatory effects of etanercept in a model of brain injury act through attenuation of the acute-phase response. |
| title_sort | immunomodulatory effects of etanercept in a model of brain injury act through attenuation of the acute phase response |
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