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


METHODS
Primary mouse neuronal cell cultures, ELISA, Western blot and immunocytochemistry techniques were used.


RESULTS
We show here that IL-1beta 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-1beta-induced Src kinase activation triggers the phosphorylation of the NMDA receptor NR2B subunit, leading to activation of Ca(2+)/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-1beta-induced IL-6 synthesis in neurones.


CONCLUSIONS
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-1beta induces IL-6 synthesis in neurones could be critical in both physiological and pathophysiological actions of IL-1beta, and may provide a new therapeutic target for the treatment of acute CNS injury.
Faculty of Life Sciences, University of Manchester, Manchester, UK. nancy.rothwell@manchester.ac.uk
N
N
Tsakiri
I
I
Kimber
N J
NJ
Rothwell
E
E
Pinteaux
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002540:Cerebral Cortex / Q000196:embryology / Q000201:enzymology / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004789:Enzyme Activation; D053583:Interleukin-1beta / Q000378:metabolism*; D015850:Interleukin-6 / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation; D053573:Receptors, Interleukin-1 Type I / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism*
C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D053583:Interleukin-1beta; D015850:Interleukin-6; C121001:NR2B NMDA receptor; D053573:Receptors, Interleukin-1 Type I; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D019061:src-Family Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D013108:Sphingomyelin Phosphodiesterase