To this end, we studied IL-1b and Ergosterol IL-1ra mRNA in the CNS in the early stages of cr-EAE and related these to some histopathological hallmarks of inflammation in the affected grey and white matter. The present study is the first to demonstrate that during the early clinical phases of experimental MS, i.e. cr-EAE, IL-1b and IL-1ra mRNA and protein are not only expressed in white matter, but also in specific grey matter areas within the CNS, which are also positive for CD68 and Oil-Red O. The IL-1b and IL-1ra mRNA expressing cells were identified as macrophages and/or endogenous activated microglial cells. In more recent years, it has become evident that within the CNS of MS patients besides white also grey matter lesions are present, which can explain more extensively certain neurological and psychiatric symptoms observed in those patients. As inflammatory processes take part in the pathogenesis of MS, we questioned whether an important inflammatory mediator, IL-1b and, its functional counteracting partner, IL-1ra are present in affected WM and GM regions in the CNS during cr-EAE in DA rats, an experimental animal model, mimicking some pathological aspects of relapsing-remitting MS. Indeed, inflammatory processes, i.e. an influx of monocytes, and to a lesser extent T-cells, as well as activation of local microglial cells are clearly present in WM and GM at the early stages of cr-EAE studied. Moreover, some demyelination is observed, but limited to periventricular and perivascular locations at these time-points. These observations are in accordance with Ginsenoside-F2 previous studies showing that demyelination is sparse whereas inflammation is prominent during early cr-EAE in DA rats. Although this may be a limitation of the model used, inflammatory mediators, including IL-1b, are known to be upregulated early in inflammatory processes and contribute to the subsequent process of demyelination. By using in situ hybridization and immunohistochemical approaches, we were able to detect IL-1b and IL-1ra expressing cells in cr-EAE affected GM regions. In addition, cerebral white matter fiber bundles and WM in the spinal cord were affected and showed IL1b and IL-1ra expressing cells. Within brain regions, most expression was detected close to veins or ventricles. The presence of IL-1b and IL-1ra mRNA was observed in close association, regionally and temporally, with the occurrence of infiltrating monocytes/activated microglia and was absent in control rats or normal appearing WM and GM. The appearance of IL-b and IL-1ra expressing cells in WM areas within the brain of our experimental MS model is consistent with elevated IL-1b and IL-1ra expression in active WML in post-mortem brain material of MS patients and of the marmoset EAE model for MS. Furthermore, IL-1b and IL1ra production within the ventricular choroid plexus is in line with observations that IL-1b production within the choroid plexus is significantly increased during the early phase of EAE in mice. Moreover, IL-1b and IL-1ra protein levels are significantly enhanced in the cerebrospinal fluid of MS patients. Our results suggest the possibility that treatment with IFNabased regimens without viral clearance may be associated with progressive liver disease.