Gene regulation by IL-1beta independent of IL-1R1 in the mouse brain

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-1alpha and IL-1beta, 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-1beta independently of IL-1R1. IL-1beta 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-1beta in wild-type, but not in IL-1R1-/- mixed glia. Amongst the other genes for which expression was modified by IL-1beta in IL-1R1-/- cells, we selected alpha-syntrophin and demonstrated by real-time quantitative PCR that expression of this gene is significantly downregulated by IL-1beta in primary mixed glia prepared from wild-type, IL-1R1-/-, IL-1RAcP-/- or MyD88-/- mice. In contrast, IL-1alpha fails to downregulate alpha-syntrophin expression in wild-type or IL-1R1-/- mixed glia. These results show that IL-1beta exclusively downregulates alpha-syntrophin expression independently of IL-1R1, and suggest the expression of additional functional IL-1 receptors in the CNS.