title: Dexamethasone regulation of interleukin-1-receptors in the hippocampus of Theiler's virus-infected mice: effects on virus-mediated demyelination.
abstract: Intracerebral (i.c.) inoculation of susceptible strains of mice with Theiler's murine encephalomyelitis virus (TMEV) results in immune-mediated demyelinating disease. Interleukin-1 receptors are expressed in the brain of mice, in particular in the hippocampus, and have been implicated in neuroimmunoendocrine 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-infection (10 and 14 days p.i.). The reduction in interleukin-1 receptors only 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-regulation of interleukin-1 receptors was secondary to a marked decrease in the affinity of the receptor (control: Kd = 10.5 pM; TMEV: Kd = 1.30 pM) accompanied by a decrease in receptor number (control: Bmax = 2.189 fmol/mg protein; 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 phase (500 microg/kg or 1 mg/kg during days 5-10 p.i.) of the disease significantly reversed the deficits in hippocampal interleukin-1 receptors observed at 10 days p.i. in SJL/J mice, and suppressed neurological signs of demyelination. These results suggest that: (i) the reduction of interleukin-1 receptors may be a consequence, at least in part, of local production of interleukin-1 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 ability to reverse the reduction in interleukin-1 receptors during the early disease. These results suggest that interleukin-1 is a pivotal mediator in TMEV-induced demyelination.
authors.affiliation: Department of Neural Plasticity, Cajal Institute, CSIC, Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Lledó
authors.forename: J
authors.initials: J
authors.lastname: Borrell
authors.forename: C
authors.initials: C
authors.lastname: Guaza
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D003711:Demyelinating Diseases / Q000473:pathology / Q000517:prevention & control / Q000821:virology; D003907:Dexamethasone / Q000494:pharmacology*; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D011051:Poliomyelitis / Q000503:physiopathology* / Q000821:virology; D017472:Receptors, Interleukin-1 / Q000187:drug effects* / Q000378:metabolism; D013045:Species Specificity; D017945:Theilovirus / Q000187:drug effects* / Q000254:growth & development; D013997:Time Factors
chemical_list: D000893:Anti-Inflammatory Agents; D017472:Receptors, Interleukin-1; D003907:Dexamethasone