Seite - 44 - in Advances in Neuroimmunology

BrainSci. 2016,6, 18 atopy in theperiphery [2–17]. IL-13andIL-4alsohave theability todownregulate thesynthesisof T-helper type1 (Th1) lymphocytepro-inflammatorycytokines: for this reasontheyarenormally listed as anti-inflammatory interleukins [8–10,15,18–20]. Both cytokines areproducedbyTh2, aswell as byothercell types, includingeosinophilsandbasophils [2,5,6,9,11–13]andIL-13production isalso stimulated inmastcellsby lipopolysaccharides (LPS) [21–24]. IL-13andIL-4areoften investigated togetherbecause theypartiallyshareacommonreceptor type: theIL-13receptoralpha1chain(IL-13Rα1). IL-13Rα1heterodimerizeswiththeIL-4Ralphachain (IL-4Rα) formingacomplexcapableofbindingIL-13or IL-4 (Figure1) [25–32]. Todate, thiscomplex is theonlyknownsignal transducer for IL-13,while IL-4canalsosignal throughanIL-4Rα/gamma chaincomplex.Ahigh-affinity IL-13-bindingprotein (IL-13Rα2)alsoexistsandisaspecific inhibitor of IL-13signaling, likelybyfunctioningasadecoyreceptor [28,33–36]. IL-13Rα2 isnot foundinthe healthybrainand,so far,hasonlybeenshowntobeexpressedintheCNSonglioblastomacells [37] making itoneof themajor targetsof immunotherapy.WorkonIL-13Rα2 in theCNSandits roleas a therapeutic targetwillnotbediscussedhereandiscoveredbyrecentexcellent reviews[38]. Figure1.Schematic representationof theheterodimeric receptor for IL-13andIL-4anditssignaling. Interleukins13 (IL-13)and4(IL-4) canbindto thesameheterodimeric receptorcomposedof the IL-13 Receptoralpha1 (IL-13Rα1)andthe Interleukin4Receptoralpha (IL-4Rα). Bindingof thereceptor activates the Januskinase (JAK)andleads tophosphorylationofmembersof theSignalTransducer andActivatorofTranscription(STAT) family. The tyrosine-proteinkinase2 (TYK2) isamemberof the JAKfamily. See the text formoredetails. Bindingof IL-13 to its cognate functional receptorallowsthe trans-phosphorylationofaspecific tyrosineresiduelocatedintheJanusKinase(JAK)activationsegment[31,39]whichpromotesthekinase activityrequiredfor thephosphorylationofdownstreamsubstrates in its signalingcascades [39,40]. IL-13activates twointracellularsignalingcascades: theJAK-STATandthe insulinreceptorsubstrate (IRS)-phosphatidylinositol31-kinasepathways[26,28,31].While the IRS-phosphatidylinositol31-kinase pathway leads to cell proliferation, the JAK-STAT pathway induces the transcription of genes that contain the Stat6-responsive enhancer element N6-GAS located in their promoter [41–43]. Uponactivationof IL-13Rα1,Stat1,3,and6arephosphorylatedandformahomodimerthatmigrates to thenucleusandbindstoN6-GAStodrivetranscription[31,42,44,45].Reactiveoxygenspecies(ROS)also playarole in theIL-13/IL-4cellular transductionsignaling. In intestinalepithelial cellsuponIL-13Rα1 activation both the JAK-STATpathway andMitogenActivated ProteinKinase (MAPK) stimulate nicotinamideadeninedinucleotidephosphateoxydase toproduce intracellularROSthat, inapositive feedback loop, facilitate thephosphorylationofSTAT6andERK[46]. Moreover, IL-13/IL-4-driven 44