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The role of interleukin-1 receptors in brain cell signalling

Nguyen, Loan

[Thesis]. Manchester, UK: The University of Manchester; 2010.

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Abstract

IL-1α and IL-1β are two IL-1 agonists which signals at the same receptor complex composed of IL-1R1/IL-1RAcP. However, IL-1α and IL-1β exert differential actions. A recent CNS-specific IL-1 receptor accessory protein, called IL-1RAcPb, has been characterised but its actions are unknown. In T cell line, over expression of IL-1RAcPb negatively regulate IL-1 action (Smith et al, 2009), but over-expression of IL-1RAcPb in HEK cell line induces IL-1 signaling (Lu et al, 2008). The role of IL-1RAcPb has not been studied in primary cells. The aim of this project was to investigate the role of IL-1RAcPb in IL-1-induced actions in neurones and glia, and to determine IL-1α and IL-1β differential actions in these two cell types. The role of IL-1RAcPb in IL-1-induced protein expression and IL 1α and IL-1β differential effects were investigated by treating WT and IL 1RAcPb-/- neurones and glia with IL-1α or IL-1β in the presence or absence of IL-1RA for 24 h followed by assessment of IL-6 induction by ELISA. The mechanism of IL-1RAcPb actions were studied by examining the effects of IL-1α or IL-1β on p38, ERK1/2 and Src kinase activation in neurones and glia by Western blot analysis. SB203580 (p38 inhibitor), UO126 (ERK1/2 inhibitor), and PP2 (Src kinase inhibitor) were used to determine the contribution of p38, ERK1/2 and Src kinase activation to IL-1-induced IL-6 synthesis in neuronal cultures. In WT neurones, IL-1α and IL-1β were equipotent at inducing IL-6 synthesis and p38 activation, whilst both ligands failed to induce ERK1/2 or Src kinase activation. In IL-1RAcPb-/- neurones, IL-1α and IL-1β induced similar levels of IL-6, but IL-1β was more potent than IL-1α at inducing p38 activation. IL-1α-induced p38 activation was reduced in IL-1RAcPb-/- neurones compared to WT neurones. In contrast to WT neurones, ERK1/2 was activated in IL-1RAcPb-/- neurones in response to IL-1α, whilst Src kinase was not activated by IL-1α or IL 1β. IL-1-induced IL-6 synthesis was abolished by IL-1RA, SB203580, UO126 and PP2. Interestingly PP2, a specific Src kinase inhibitor also partially inhibited basal ERK1/2 activity. In WT glial cells, IL-1α was more potent than IL-1β at inducing IL-6 synthesis but both cytokines induced ERK1/2 activation with equal potency. In IL-1RAcPb-/- glia, IL-1α and IL-1β were equally potent at inducing IL-6 synthesis and ERK1/2 activation. However, IL-α-induced-IL-6 synthesis was reduced in IL 1RAcPb-/- glia compared to WT glia. In both WT and IL-1RAcPb-/- glia, IL-1α and IL-1β induced p38 activation but not Src kinase activation . In conclusion, this study showed that in neurones, IL-1RAcPb may contribute to IL-1α-induced p38 activation but negatively regulates IL-1-induced ERK1/2 activation, therefore IL-1RAcPb may have specific effects on different signalling pathways. The effect of IL-1RAcPb could also be cell specific, as IL 1RAcPb contributed to IL-1α-induced p38 signalling in neurones but IL-6 production in glia. The role of IL-1RAcPb remains largely unknown and more investigations are required to elucidate its role in IL-1 signalling in the brain.