Immunomodulatory effects of etanercept in a model of brain injury act through attenuation of the acute-phase response

J Neurochem. 2007 Dec;103(6):2245-55. doi: 10.1111/j.1471-4159.2007.04928.x. Epub 2007 Sep 18.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease / therapy
  • Acute-Phase Reaction / prevention & control*
  • Animals
  • Brain / drug effects*
  • Brain / immunology
  • Brain / physiopathology
  • Brain Injuries / drug therapy*
  • Brain Injuries / immunology
  • Brain Injuries / physiopathology
  • Chemokines / drug effects
  • Chemokines / genetics
  • Chemokines / metabolism
  • Disease Models, Animal
  • Encephalitis / drug therapy*
  • Encephalitis / immunology
  • Encephalitis / physiopathology
  • Etanercept
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Immunoglobulin G / pharmacology*
  • Immunosuppressive Agents / pharmacology*
  • Inflammation Mediators / pharmacology
  • Liver / drug effects
  • Liver / immunology
  • Liver / metabolism
  • Male
  • Rats
  • Rats, Wistar
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Chemokines
  • Immunoglobulin G
  • Immunosuppressive Agents
  • Inflammation Mediators
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • Etanercept