Differential effects of interleukin-1 alpha and beta on interleukin-6 and chemokine synthesis in neurones

Interleukin (IL)-1 is a key mediator of neuroinflammation via actions of two agonists IL-1 alpha and beta that bind to the IL-1 type I receptor (IL-1RI), and are thought to trigger identical responses. However, evidence suggests that IL-1 alpha and beta may have differential actions in the central nervous system (CNS). The objective of this study was to test the hypothesis that IL-1 alpha and beta differentially regulate the expression of IL-6 and chemokines KC, IP-10 and MCP-1 in primary neurones. Here we demonstrate that, whilst IL-1 beta induced significant synthesis of IL-6 in neurones, IL-1 alpha had no effect. In contrast, IL-1 alpha and 0 induced strong synthesis and constitutive release of chemokines KC, IP-10 and MCP-1 from neurones, and these responses were IL-1RI-dependent. Whilst IL-1 beta-induced IL-6 synthesis was dependent on the nSMase/Src kinase signalling cascade, specific inhibitors of nSMase (3-OMS) and Src kinase (PP2) failed to inhibit IL-1 alpha- and IL-1 beta-induced chemokines synthesis, suggesting the existence of alternative signalling pathway(s) in neurones. (C) 2008 Elsevier Inc. All rights reserved.