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Immunomodulatory effects of etanercept in a model of brain injury act through attenuation of the acute‐phase response
Author(s) -
Campbell Sandra J.,
Jiang Yanyan,
Davis Andrew E. M.,
Farrands Rebecca,
Holbrook Joanna,
Leppert David,
Anthony Daniel C.
Publication year - 2007
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2007.04928.x
Subject(s) - chemokine , medicine , etanercept , immunology , tumor necrosis factor alpha , immune system , lipopolysaccharide , acute phase protein , inflammation , alpha (finance) , blood–brain barrier , central nervous system , construct validity , nursing , patient satisfaction
TNF‐α 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‐α strategies may offer promise as therapy for non‐immune CNS injury. In this study, we have microinjected IL‐1β or lipopolysaccharide (LPS) into the rat brain as a simple model of brain injury and have systemically administered the TNF‐α antagonist etanercept to discover whether hepatic TNF‐α, 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‐1β‐ or LPS‐challenged brain as a result of TNF‐α inhibition. We also show an attenuation in the levels of hepatic mRNA including TNF‐α mRNA and of TNF‐α‐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‐α 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.