Interleukin‐1‐induced interleukin‐6 synthesis is mediated by the neutral sphingomyelinase/Src kinase pathway in neurones

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Abstract
Background and purpose: Interleukin (IL)‐1 is a key mediator of inflammatory and host defence responses and its effects in the brain are mediated primarily via effects on glia. IL‐1 induces release of inflammatory mediators such as IL‐6 from glia via the type‐1 receptor (IL‐1R1) and established signalling mechanisms including mitogen‐activated protein kinases and nuclear factor kappa‐B. IL‐1 also modifies physiological functions via actions on neurones, through activation of the neutral sphingomyelinase (nSMase)/Src kinase signalling pathway, although the mechanism of IL‐1‐induced IL‐6 synthesis in neurones remains unknown. Experimental approach: Primary mouse neuronal cell cultures, ELISA, Western blot and immunocytochemistry techniques were used. Key results: We show here that IL‐1β induces the synthesis of IL‐6 in primary mouse neuronal cultures, and this is dependent on the activation of IL‐1R1, nSMase and Src kinase. We demonstrate that IL‐1β‐induced Src kinase activation triggers the phosphorylation of the NMDA receptor NR2B subunit, leading to activation of Ca2+/calmodulin‐dependent protein kinase II (CamKII) and the nuclear transcription factor CREB. We also show that NR2B, CamKII and CREB are essential signalling elements involved in IL‐1β‐induced IL‐6 synthesis in neurones. Conclusions and implications: These results demonstrate that IL‐1 interacts with the same receptors on neurones and glia to elicit IL‐6 release, but does so via distinct signalling pathways. The mechanism by which IL‐1β induces IL‐6 synthesis in neurones could be critical in both physiological and pathophysiological actions of IL‐1β, and may provide a new therapeutic target for the treatment of acute CNS injury. British Journal of Pharmacology (2008) 153, 775–783; doi:10.1038/sj.bjp.0707610; published online 3 December 2007