Dexamethasone regulation of interleukin-1-receptors in the hippocampus of Theiler's virus-infected mice: effects on virus-mediated demyelination

Intracerebral (i.c.) inoculation of susceptible strains of mice with Theile r's murine encephalomyelitis virus (TMEV) results in immune-mediated demyel inating disease. Interleukin-1 receptors are expressed in the brain of mice , in particular in the hippocampus, and have been implicated in neuroimmuno endocnine interactions. In the present study we investigated the regulation of interleukin-1 receptors in the hippocampus of a susceptible (SJL/J) and a resistant (BALB/c) strain of mice infected with TMEV, at different time intervals of the disease. Our results show that interleukin-1 receptors in the hippocampus were decreased in TMEV-infected mice at early times post-in fection (10 and 14 days p.i.). The reduction in interleukin-1 receptors onl y occurred in the susceptible strain of mice (SJL/J), whereas Interleukin-1 binding in the hippocampus of TMEV-infected resistant mice (BALB/c) showed values similar to those in control animals. The TMEV-induced down-regulati on of interleukin-1 receptors was secondary to a marked decrease in the aff inity of the receptor (control: K-d, = 10.5 pM; TMEV: K-d, = 1.30 pM) accom panied by a decrease in receptor number (control: B-max = 2.189 fmol/mg pro tein; TMEV: B-max = 0.84 fmol/mg protein). We also investigated the effects of glucocorticoid treatment on the regulation of hippocampal interleukin-1 receptors of TMEV-infected mice. Dexamethasone treatment in the early phas e (500 mu g/kg or 1 mg/kg during days 5-10 p.i.) of the disease significant ly reversed the deficits in hippocampal interleukin-1 receptors observed at 10 days p.i, in SJL/J mice, and suppressed neurological signs of demyelina tion. These results suggest that: (i) the reduction of interleukin-1 recept ors may be a consequence, at least in part, of local production of interleu kin-l at early times during TMEV infection; (ii) interleukin-1 seems to be a critical factor for the susceptibility to TMEV-induced demyelination and (iii) the protective effect of dexamethasone appears to be related to its a bility to reverse the reduction in interleukin-l receptors during the early disease. These results suggest that interleukin-1 is a pivotal mediator in TMEV-induced demyelination, (C) 1999 Elsevier Science B.V. All rights rese rved.