Abstract
Interleukin‐1 (IL‐1) is a key pro‐inflammatory cytokine that has diverse actions in the brain as a regulator of host defense responses and a mediator of inflammation. Two major agonists, IL‐1α and IL‐1β, bind to a single known functional type‐1 IL‐1 receptor (IL‐1RI) that associates with the accessory protein (IL‐1RAcP), resulting in signal transduction. However, recent evidence suggests that some actions of IL‐1 in the brain may be independent of IL‐1R1 and the classical IL‐1 signaling pathways, pointing to an as‐yet unidentified functional receptor for IL‐1. In this study, we have used cDNA microarray‐based gene expression profiling to identify the possible genes induced by IL‐1β independently of IL‐1R1. IL‐1β induced potential changes (greater than 2‐fold vs. vehicle‐treated) in the expression of up to 1285 candidate genes in wild‐type primary mixed glia, and 404 candidate genes in IL‐1R1^−/−^ cells of the same type. Real‐time quantitative polymerase chain reaction (PCR) on selected genes revealed that pentraxin‐3, was upregulated by IL‐1β in wild‐type, but not in IL‐1R1^−/−^ mixed glia. Amongst the other genes for which expression was modified by IL‐1β in IL‐1R1^−/−^ cells, we selected α‐syntrophin and demonstrated by real‐time quantitative PCR that expression of this gene is significantly downregulated by IL‐1β in primary mixed glia prepared from wild‐type, IL‐1R1^−/−^, IL‐1RAcP^−/−^ or MyD88^−/−^ mice. In contrast, IL‐1α fails to downregulate α‐syntrophin expression in wild‐type or IL‐1R1^−/−^ mixed glia. These results show that IL‐1β exclusively downregulates α‐syntrophin expression independently of IL‐1R1, and suggest the expression of additional functional IL‐1 receptors in the CNS. © 2005 Wiley‐Liss, Inc.