Page - 3 - in Advances in Neuroimmunology

BrainSci. 2016,6, 19 consequently trans-signalinggreatlyexpands the targetareaof IL-6actions. Trans-signalingappears tobe theprimarypathwayinvolvedin thepathologicalactionsof IL-6 in theCNS[42]. Figure 1. Diagrams showing signal transduction pathways used by chemokines and the proinflammatorycytokine IL-6.Aplussignwithinacircle indicatesactivationof the targetmolecule andaminussignwithinacircle indicates inhibitionof the targetmolecule. (A)Agonistbindingto the G-proteincoupledreceptors (GPCR) initiatesdissociationof theG-proteinheterotrimercoupledto the receptor intoGαandGβγsubunits. TheGαandGβγsubunits thenactivateor inhibitdownstream effectors. These effectors include ion channels, such as voltage-gated calcium channels (VGCC), andsignal transductionmolecules includingphospholipaseC (PLC)andadenylate cyclase (Acyc). ActivationofPLCleads to theproductionofothersignalingmolecules includingdiacylglycerol (DAG) andinositol trisphosphate (IP3), anddownstreamactivationofproteinkinaseC(PKC)andinositol trisphosphatereceptors (IP3R),whichregulate thereleaseofcalciumfromintracellular stores; (B) IL-6 cansignal througheitheramembranebound(classic signaling)orasoluble (trans-signaling) IL-6R. TheIL-6/IL-6Rcomplex interactswithgp130 toactivate the JAK/STATsignalingpathway. Inaddition, the IL-6/IL-6R/gp130complexcanactivateRAS/mitogen-activatedproteinkinase (p44/42MAPK, alsocalledERK1/2;MAPK)andphosphatidylinositol-3kinase (PI3K)signalingpathways.All three signalingpathwaysactivateadditionaldownstreamsignalingmoleculesandeffectors. 3