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-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.
Campbell
Sandra J
SJ
Experimental Neuropathology, Department of Pharmacology, University of Oxford, Oxford, UK.
Jiang
Yanyan
Y
Davis
Andrew E M
AE
Farrands
Rebecca
R
Holbrook
Joanna
J
Leppert
David
D
Anthony
Daniel C
DC
D000208:Acute Disease / Q000628:therapy; D000210:Acute-Phase Reaction / Q000517:prevention & control*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000276:immunology / Q000503:physiopathology; D001930:Brain Injuries / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D018925:Chemokines / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004660:Encephalitis / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D000068800:Etanercept; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D007074:Immunoglobulin G / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D018925:Chemokines; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept