Recombinant human interleukin-1 induces meningitis and blood-brain barrier injury in the rat. Characterization and comparison with tumor necrosis factor.
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.
Quagliarello
V J
VJ
Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville 22908.
Wispelwey
B
B
Long
W J
WJ
Scheld
W M
WM
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D007249:Inflammation / Q000139:chemically induced; D007276:Injections, Intraventricular; D007375:Interleukin-1 / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D008581:Meningitis / Q000134:cerebrospinal fluid / Q000139:chemically induced* / Q000473:pathology; D010539:Permeability; D011112:Polymyxin B / Q000494:pharmacology; D051381:Rats; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity
D007375:Interleukin-1; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D011112:Polymyxin B