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

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-1b 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-1b-induced Src kinase activation triggers the phosphorylation of the NMDA receptor NR2B subunit, leading to activation of Ca 2 þ /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-1b-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-1b induces IL-6 synthesis in neurones could be critical in both physiological and pathophysiological actions of IL-1b, and may provide a new therapeutic target for the treatment of acute CNS injury.

Involvement of nuclear factor-κB in macrophage migration inhibitory factor gene transcription up-regulation induced by interleukin-1β in ectopic endometrial cells

“…the local peritoneal endometriosis-associated immunoinflammatory reaction. In addition, several studies showed that IL1b activates other transcription factors including activator protein-1 and cyclic AMP response element binding protein (45,46) and it will be very interesting to investigate the involvement of these factors in MIF regulation. Recent data also showed that the promoter of MIF contains putative binding sites for these two transcription factors (47) and that cyclic AMP response element binding protein positively regulates MIF promoter activity (48).…”

Contribution of Interleukin-1 Receptor Accessory Protein b to Interleukin-1 Actions in Neuronal Cells

“…We have reported previously that IL-1 ␣ and IL-1 ␤ induce glial cell production of IL-6 via activation of the mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase 1/2 (ERK1/2), p38 and c-Jun N-terminal kinase [9,10] . Neuronal cells also respond to IL-1 to produce IL-6, which is mediated in part by the Src kinase signaling pathway [11] . Although the signaling mechanisms of IL-1 in glial cells are generally well characterised, the precise Interleukin-1 Signaling in Neurons Neurosignals 2011;19:222-230 223 signaling mechanism of IL-1 in neurons remains elusive.…”

The Role of Cytokines in the Regulation of Neurotransmission

“…The idea that neurons produce cytokines has been accepted recently [26] . For instance, studies conducted in vitro have documented that fetal rat dorsal root ganglion neurons produce IFN-␥ and express its receptor [27,28] .…”