Recombinant human interleukin-1 induces meningitis and blood-brain barrier injury in the rat. Characterization and comparison with tumor necrosis factor

J Clin Invest. 1991 Apr;87(4):1360-6. doi: 10.1172/JCI115140.

Abstract

The diversity of infectious agents capable of inducing meningitis and blood-brain barrier (BBB) injury suggests the potential for a common host mediator. The inflammatory polypeptides, IL-1 and TNF, were tested in an experimental rat model as candidate mediators for induction of meningitis and BBB injury. Intracisternal challenge of rIL-1 beta into rats induced neutrophil emigration into cerebrospinal fluid (CSF) and significantly increased BBB permeability to systemically administered 125I-BSA as early as 3 h later (P less than 0.05). This injury was reversible, dose dependent and significantly inhibited by prior induction of systemic neutropenia (via intraperitoneal cyclophosphamide) or preincubation of the rIL-1 beta inoculum (50 U) with an IgG monoclonal antibody to rIL-1 beta. Similar kinetics and reversibility of CSF inflammation and BSA permeability were observed using equivalent dose inocula of rIL-1 alpha. rTNF-alpha was less effective as an independent inducer of meningitis or BBB injury over an inoculum range of 10(1) U (0.0016 micrograms/kg)-10(6) U (160 micrograms/kg) when injected intracisternally, but inoculum combinations of low concentrations of rTNF alpha (10(3) U) and rIL-1 beta (0.0005-5.0 U) were synergistic in inducing both meningitis and BBB permeability to systemic 125I-BSA. These data suggest that in situ generation of interleukin-1 within CSF (with or without TNF) is capable of mediating both meningeal inflammation and BBB injury seen in various central nervous system infections.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blood-Brain Barrier / drug effects*
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Inflammation / chemically induced
  • Injections, Intraventricular
  • Interleukin-1 / administration & dosage
  • Interleukin-1 / pharmacology
  • Interleukin-1 / toxicity*
  • Meningitis / cerebrospinal fluid
  • Meningitis / chemically induced*
  • Meningitis / pathology
  • Permeability
  • Polymyxin B / pharmacology
  • Rats
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha / toxicity

Substances

  • Interleukin-1
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha
  • Polymyxin B