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 I-125-BSA as early as 3 h later (P < 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 or 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-mu-g/kg)-10(6) U (160-mu-g/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 I-125-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.