Interleukin-4 mediates the neuroprotective effects of rosiglitazone in the aged brain

Increased expression of proinflammatory cytokines, like interleukin-1β (IL-1β), is a feature of the aged brain and it is generally accepted that the primary cell source of these cytokines is activated microglia. In hippocampus of aged rats, the increase in IL-1β is accompanied by microglial activation and impaired long-term potentiation (LTP). Peroxisome proliferator-activated receptors (PPARs) possess anti-inflammatory properties that target microglia. In this study the PPARγ agonist, rosiglitazone, was orally administered to young and aged rats, and we report that the age-related increases in NO and IL-1β production were attenuated in hippocampus of rosiglitazone-treated aged rats and that this was associated with a restoration of LTP. In addition, treatment with rosiglitazone increased interleukin-4 (IL-4) mRNA and reversed the age-related decrease in hippocampal IL-4 concentration. Significantly, while rosiglitazone attenuated the LPS-induced increase in MHCII and IL-1β concentration in glia prepared from wildtype mice, it failed to exert an effect in glia prepared from IL-4−/− mice, thereby suggesting that the anti-inflammatory actions of rosiglitazone are mediated by its ability to increase IL-4 expression.