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Wat is die onderskeid tussen chemokiene, sitokiene, interferone en interleukiene?

Wat is die onderskeid tussen chemokiene, sitokiene, interferone en interleukiene?


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Dit lyk asof hulle almal molekules met soortgelyke funksie beskryf en dit lyk asof baie mense dit uitruilbaar gebruik.

Sluit asseblief ook enige ander soortgelyke molekules in as ek enige in die lys hierbo vergeet het.


Sitokiene is die algemene klas molekules waaraan chemokiene, interferone, interleukiene en ander behoort. Bioloë betwis of iets 'n hormoon of 'n sitokien is, maar oor die algemeen gaan die konsensus saam as dit met immunologie te doen het, dit is 'n sitokien of as die rustende konsentrasie in die pikomolêre reeks is, maar dit is 'n baie growwe onderskeid.

Chemokiene is molekules wat sellulêre chemotaksis aandryf. Dit beteken dat hulle selle na 'n gewenste plek laat beweeg. Oor die algemeen verwys chemokiene na immuunselle en daar is baie en baie daarvan.

Interleukiene is enigiets wat boodskappermolekules tussen immuunselle is (inter- beteken tussen en -leukiene beteken leukosiete/witbloedselle). Hulle word tipies aangedui deur IL + nommer. Die interferon- en tumornekrosefamilies kom egter ook onder interleukiene volgens die meeste mense se mening. Die interferone is 'n spesiale groep wat tipies virusse inhibeer deur selle nie toelaatbaar vir virale replikasie te maak nie. Hulle doen ook 'n paar ander dinge soos om makrofage te aktiveer of Th1-reaksie te bevorder, wat albei ook met virusse inmeng, maar daar is bakteriese oorvleueling. Die TNF-familie is 'n bietjie vreemder aangesien sommige interleukienagtig is, maar ander is nie so baie nie. TNF-alfa (die klassieke een) is betrokke by makrofaag rypwording. Nie alle interleukiene is egter streng tussen witbloedselle nie, aangesien IL1 op die hipotalamus onder ander leukosiete inwerk.

Sien die probleem is dat alles 'n bietjie grys is, want die meeste sitokiene (indien nie almal nie) het meer as een rol en daar is nooit konsensus in die wêreld van immunologie wanneer dit by sitokiene kom nie, want al hoe meer word steeds ontdek.


Kortliks, dit is my begrip na aanleiding van my immunologiekursus (wat meestal identies is aan AndroidPenguin se antwoord):

  • Chemokiene: Produseer selbeweging, d.w.s. tree op as chemoattraktante. Tipies word dit gebruik om meer immuunselle na 'n plek van infeksie te werf. (Naam oorsprong sê dit alles: "chemotaktiese sitokien = chemokien...)

  • Sitokiene: Produseer 'n inflammatoriese reaksie deur die verandering van transkripsie (via oppervlak reseptor sein kaskades). Dit werk dikwels op nie-immuun selle.

    • Interferone: 'n Soort sitokien. Geskei deur feitlik elke sel in reaksie op besmetting deur 'n virus. Produseer 'n 'anti-virale' toestand in ander selle, deur BAIE meganismes. Veroorsaak die tipiese griepagtige simptome.

    • Tumornekrosefaktore (spesifiek TNF alfa): 'n Tipe sitokien. Berei endoteel (bloedvatwande) voor om 'n inflammatoriese reaksie te ondersteun deur vasodilatasie, verhoogde adhesie en verhoogde deurlaatbaarheid.

  • Interleukiene: Sommige is chemokiene (bv. afgeskei deur makrofage en dendritiese selle na aktivering om verdere fagosiete en aanpasbare immuunselle te werf), ander is sitokiene (bv. aktiveer B-selle om te differensieer na plasma en geheueselle na T-sel kontak).


Farmakologie kruisverwysing: Rekombinante tipe I interferone word as terapeutika ingespuit. Virale infeksies lyk soos logiese aanduidings, maar interferone is beide duur en het aansienlike nadelige effekte, bv. bv. griepagtige simptome by inspuiting, bloedarmoede en depressie. Die toepassing daarvan is dus beperk tot lewensgevaarlike virussiektes, bv. g. hepatitis C.


11.3C: Sitokiene belangrik in aangebore immuniteit

  • Bygedra deur Gary Kaiser
  • Professor (Mikrobiologie) by Community College of Baltimore Country (Cantonsville)

Sitokiene is lae molekulêre gewig, oplosbare proteïene wat geproduseer word in reaksie op 'n antigeen en funksioneer as chemiese boodskappers vir die regulering van die aangebore en aanpasbare immuunstelsels. Hulle word geproduseer deur feitlik alle selle wat betrokke is by aangebore en aanpasbare immuniteit, maar veral deur T-helper (Th) limfosiete. Die aktivering van sitokienproduserende selle veroorsaak dat hulle hul sitokiene sintetiseer en afskei. Die sitokiene kan dan op hul beurt aan spesifieke sitokienreseptore op ander selle van die immuunstelsel bind en hul aktiwiteit op een of ander manier beïnvloed.

Sitokiene is pleiotropies, oortollig en multifunksioneel.

  • Pleiotroop beteken dat 'n spesifieke sitokien op 'n aantal verskillende tipes selle kan inwerk eerder as 'n enkele seltipe.
  • Redundant verwys na die vermoë van 'n aantal verskillende sitokiene om dieselfde funksie uit te voer.
  • Multifunksioneel beteken dieselfde sitokien is in staat om 'n aantal verskillende funksies te reguleer.

Sommige sitokiene is antagonisties deurdat een sitokien 'n spesifieke verdedigingsfunksie stimuleer terwyl 'n ander sitokien daardie funksie inhibeer. Ander sitokiene is sinergisties waarin twee verskillende sitokiene 'n groter effek in kombinasie het as wat een van die twee op sigself sou. Daar is drie funksionele kategorieë sitokiene:

1. sitokiene wat aangebore immuunresponse reguleer,
2. sitokiene wat aanpasbare immuunresponse reguleer, en
3. sitokiene wat hematopoïese stimuleer.

Sitokiene wat aangebore immuniteit reguleer, word hoofsaaklik deur mononukleêre fagosiete soos makrofage en dendritiese selle geproduseer, hoewel hulle ook deur T-limfosiete, NK-selle, endoteelselle en mukosale epiteelselle geproduseer kan word. Hulle word hoofsaaklik geproduseer in reaksie op patogeen-geassosieerde molekulêre patrone (PAMPs) soos LPS, peptidoglikaan monomere, teichoïne sure, ongemetileerde sitosien-guanien dinukleotied- of CpG-volgordes in bakteriese en virale genome, en dubbelstrengs virale RNA. Sitokiene wat in reaksie op PRR'e op seloppervlaktes geproduseer word, soos die inflammatoriese sitokiene IL-1, IL-6, IL-8 en TNF-alfa, werk hoofsaaklik op leukosiete en die endoteelselle wat bloedvate vorm om te bevorder en te beheer vroeë inflammatoriese reaksies (Figuur (PageIndex<1>)). Sytokiene wat geproduseer word in reaksie op PRR's wat virale nukleïensure herken, soos tipe I interferone, blokkeer hoofsaaklik virale replikasie binne besmette gasheerselle (sien Figuur (PageIndex<2>)A en Figuur (PageIndex<2> )B).

Figuur (PageIndex<1>): Integrine op die oppervlak van die leukosiet bind aan adhesiemolekules op die binneoppervlak van die vaskulêre endoteelselle. Die leukosiete plat uit en druk tussen die endoteelselle in om die bloedvate te verlaat en die weefsel binne te gaan. Die verhoogde kapillêre deurlaatbaarheid laat ook plasma die weefsel binnedring.


'n Genomiese analise van hoendersitokiene en chemokiene

Aangesien die meeste meganismes van aanpasbare immuniteit tydens die divergensie van vertebrate ontwikkel het, verteenwoordig die immuunstelsels van bestaande gewerwelde diere verskillende suksesvolle variasies op die temas wat in hul vroegste gemeenskaplike voorouers geïnisieer is. Die gene betrokke by die uitwerking van hierdie meganismes is onderworpe aan buitengewone selektiewe druk in 'n wapenwedloop met hoogs aanpasbare patogene, wat gelei het tot hoogs uiteenlopende volgordes van ortoloë gene en die wins en verlies van lede van geenfamilies namate verskillende spesies verskillende oplossings vir die uitdaging vind. van infeksie. Gevolglik was dit moeilik om gedetailleerde kennis van die molekulêre meganismes van die soogdier-immuunstelsel na die hoender oor te dra en dus om die reeds beduidende bydrae van hoenders tot die begrip van die evolusie van immuniteit te verbeter. Die beskikbaarheid van die hoendergenoomvolgorde bied die geleentheid om uitstaande vrae op te los oor watter molekulêre komponente van die immuunstelsel tussen soogdiere en voëls gedeel word en wat hul unieke evolusionêre oplossings verteenwoordig. Ons het genoomdata met bestaande kennis geïntegreer om 'n nuwe vergelykende sensus van lede van sitokien- en chemokiengeenfamilies te maak, wat die kernstel molekules onderskei wat waarskynlik algemeen is vir alle hoër gewerwelde diere van dié wat spesifiek is tot hierdie 300 miljoen jaar oue afstammelinge. Sommige verskille kan verklaar word deur die verskillende argitekture van die soogdier- en voëlimmuunstelsels. Hoenders het nie limfknope nie en ook nie die gene vir die limfotoksiene en limftoksienreseptore nie. Die gebrek aan funksionele eosinofiele korreleer met die afwesigheid van die eotaksiengene en ons voorheen gerapporteerde waarneming dat interleukin-5 (IL-5) 'n pseudogeen is. Om op te som, in die hoendergenoom kan ons die gene identifiseer vir 23 ILs, 8 tipe I interferone (IFNs), IFN-gamma, 1 kolonie-stimulerende faktor (GM-CSF), 2 van die 3 bekende transformerende groeifaktore (TGFs) ), 24 chemokiene (1 XCL, 14 CCL, 8 CXCL en 1 CX3CL), en 10 tumor nekrose faktor superfamilie (TNFSF) lede. Reseptorgene wat in die genoom teenwoordig is, dui op die waarskynlike teenwoordigheid van 2 ander IL's, 1 ander CSF en 2 ander TNFSF-lede.


Oorsig

Sitokiene is belangrike bemiddelaars van immuunresponse en word deur byna elke sel in die liggaam geproduseer. Groeistimulerende of inhiberende sitokiene kan gesubklassifiseer word as interleukiene (ILs), limfokiene, monokiene, chemokiene en hematopoietiese groeifaktore. In kanker werk sekere sitokiene direk op die groei, differensiasie of oorlewing van endoteelselle, terwyl ander optree deur inflammatoriese seltipes aan te trek wat angiogenese beïnvloed of deur sekondêre sitokiene of ander mediators wat angiogenese reguleer, te induseer. Pro-inflammatoriese en chemotaktiese sitokiene beïnvloed die tumoromgewing en beheer die hoeveelheid en aard van infiltrerende hematopoietiese effektorselle, met inhiberende of versterkende effekte op tumorgroei. Die belangrike rol van sitokiene in die regulering van immuunresponse kan 'n effektiewe immuunrespons teen die gewasse toelaat of die funksie van antigeen-presenterende selle (APC) onderdruk.

Die begrip van sitokiene het nou na vore gekom as 'n komplekse prentjie van interaksie stimulerende en inhiberende faktore. Baie van die molekules wat hierdie proses beheer, is gekloon en het kliniese proewe aangegaan. Dit is nou duidelik dat regulatoriese sitokiene kenmerkend pleiotropies is en terselfdertyd beduidende funksionele oortolligheid vertoon.

Die biologiese karakterisering van die bekende klinies relevante ILs, interferone en geselekteerde groeifaktore, die rasionaal vir hul gebruik in terapie vir pasiënte met kanker, en die opgehoopte kliniese ervaring verteenwoordig die onderwerpe van hierdie hoofstuk.

Sitokiene, 'n diverse familie seinmolekules, is belangrike bemiddelaars van immuunreaksies en word deur byna elke sel in die liggaam geproduseer, insluitend verskeie kankerselle. Oor die algemeen is sommige sitokiene groeistimulerend en ander is inhiberend. Sitokiene met kliniese relevansie vir kanker sluit dié in wat verder gesubklassifiseer is as interleukiene (ILs), monokiene, chemokiene en hematopoietiese groeifaktore. IL dui op enige oplosbare proteïen of glikoproteïenproduk van leukosiete wat die response van ander leukosiete reguleer. IL's produseer hul effekte hoofsaaklik deur parakriene interaksies. In kanker werk sekere sitokiene direk op die groei, differensiasie of oorlewing van endoteelselle, terwyl ander optree deur inflammatoriese seltipes aan te trek wat angiogenese beïnvloed of deur sekondêre sitokiene of ander mediators wat angiogenese reguleer, te induseer. Pro-inflammatoriese en chemotaktiese sitokiene beïnvloed die tumoromgewing en beheer die hoeveelheid en aard van infiltrerende hematopoietiese effektorselle, met inhiberende of versterkende effekte op tumorgroei. Die belangrike rol van sitokiene in die regulering van immuunresponse kan 'n effektiewe immuunrespons teen die gewasse toelaat of die funksie van APC onderdruk. Vermoedelike antigene bestaan ​​op tumorselle, verskeie immunostimulerende sitokiene, en veral IL's, word nou aan pasiënte toegedien in 'n poging om 'n swak of voorheen nie-bestaande antitumor immuunrespons te inisieer, aan te vul of andersins te stimuleer. Benewens immuunresponsstimulasie, is sommige IL's gebruik om die groei en differensiasie van verskeie subpopulasies van bloedselle na chemoterapie of beenmurgoorplanting (BMT) in 'n herstellende rol te stimuleer.

Dit is nou duidelik dat die pleiotropiese aard van baie sitokiene hulle in staat stel om feitlik alle orgaanstelsels te beïnvloed (Figuur 1). Sitokiene kan hul eie private reseptor hê, maar kan ook 'n "openbare" reseptor met ander sitokiene deel (Tabelle 1 en 2).


Figuur 1 Benewens hul uitwerking op hematopoïese en immunokompetentie, beïnvloed "hematopoietiese" groeifaktore verskeie orgaanstelsels, insluitend (maar nie beperk nie tot) beenhermodellering, kardiorespiratoriese funksie, lewerfunksie en die spysverteringskanaal.

Tabel 1 Tipes hematopoietiese groeifaktorreseptore



























Tik Eienskappe Reseptor voorbeelde
Tipe I sitokienreseptor Besit nie intrinsieke kinase-aktiwiteit nie. Reseptor dien as dokplek vir adaptermolekules, wat lei tot fosforilering van sellulêre substrate IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-13, IL-18, IL-21, GM-CSF, G- CSF, EPO, TPO, en leukemie inhiberende faktor
Tipe II sitokienreseptor Bevat ekstrasellulêre fibronektien III tipe domein Interferon en IL-10
Reseptore met tyrosienkinase-domeine (tipe III) Groot ekstrasellulêre immunoglobulienagtige domein, enkel transmembraan-spingebied en 'n sitoplasmiese tyrosienkinase-domein(e) fms (M-CSF reseptor), FLT-3, c-kit (SCF reseptor) en PDGFR
Chemokienreseptor Sewe transmembraan wat oor G-proteïen-gekoppelde streke strek IL-8
Tumor nekrose faktor familie Sisteïenryke herhalings in die ekstrasellulêre domein, en sitoplasmiese 80 aminosuur "doodsdomein" Tumornekrosefaktor en Fas

Afkortings: EPO, eritropoïetien G-CSF, granulosiet kolonie-stimulerende faktor GM-CSF, granulosiet makrofaag kolonie-stimulerende faktor IL, interleukien M-CSF, makrofaag kolonie-stimulerende faktor SCF, stamsel faktor TPO, trombopoëtien.


































































































































































































































































































































































































































Chromosomale ligging Reseptors Geselekteerde biologiese aktiwiteite
IL-1 2q13 IL-1RI en IL-1RII Bevorder akute-fase reaksie. IL-1 werk op byna elke orgaanstelsel. Induseer produksie van veelvuldige sitokiene
Opreguleer sel-oppervlak sitokien uitdrukking
Sinergiseer met ander sitokiene om hematopoietiese progenitorproliferasie te stimuleer
Beïnvloed immuunregulering
Moduleer endokriene funksie
Beïnvloed beenvorming
IL-1R dien as 'n kofaktor in neurale oordrag
IL-2 4q26-q27 αβγ heterotrimeriese kompleks Induseer proliferasie en aktivering van T-selle, B-selle en NK-selle
IL-3 5q31 IL-3-reseptor (heterodimeer van IL-3-spesifieke α-subeenheid en β-subeenheid) Stimulering van multi-lyn hematopoietiese stamvaders, veral wanneer dit gebruik word in kombinasie met ander sitokiene (SCF, IL-1, IL-6, G-CSF, GM-CSF, EPO en TPO)
IL-4 en IL-13 5q31 Tipe I IL-4 reseptor (IL-4Ra en IL-2 reseptor γ c ketting subeenhede) transduseer IL-4 IL-4 en IL-13 is betrokke by allergiese reaksies (induseer oorskakeling na IgE)
Tipe II IL-4 reseptor (IL-4Ra en die IL-13 Rα1 subeenhede) transduseer IL-4 en IL-13
IL-4Ra en IL-13 Rα2 kompleks of twee IL-13 Ra transduce IL-13
IL-5 5q31 Bestaan ​​uit IL-5Ra (IL-5-spesifiek) en 'n β-subeenheid Reguleer produksie, funksie, oorlewing en migrasie van eosinofiele
β subeenheid is algemeen vir IL-3 en GM-CSF komplekse Verbeter basofielgetal en -funksie
IL-6 7p21 IL-6Ra saam met gp130 B- en T-sel ontwikkeling en funksie
Trombopoiese
Akute-fase proteïensintese
Inhibisie van hepatiese albumien-uitskeiding
Osteoklastiese beenresorpsie
Neurale differensiasie
IL-7 8q12-q13 Bestaan ​​uit IL-7Ra (CD127) en die algemene γc-ketting subeenhede Kritiek vir T- en B-sel ontwikkeling
IL-8 4q12-q13 IL-8Rα en IL-8Rβ bestaan Kragtige chemoattraktante middel vir 'n verskeidenheid leukosiete, veral neutrofiele
Onderdruk kolonievorming van onvolwasse myeloïde stamvaders
Verhoog keratinosiet- en endoteelselproliferasie
IL-9 5q31.1 IL-9 reseptor Ondersteun klonogeniese rypwording van eritroïed-voorlopers
Dien as 'n mastseldifferensiasiefaktor
Beskerm limfome teen apoptose
Werk saam met IL-4 in B-selreaksies
Verhoog neuronale differensiasie
IL-10 1q31-q32 IL-10 reseptor interferon reseptore Inhibeer sitokiensintese deur Th1-selle en monosiete/makrofage
Stimuleer B-sel proliferasie
Betrokke by transformasie van B-selle deur Epstein-Barr-virus en tumor nekrose faktor (TNF) reseptore
IL-11 19q13.3-q13.4 IL-11Ra en gp 130 subeenhede gp 130 = CD130 op 5q11 IL-6, onkostatien M en leukemie inhiberende faktor gebruik ook gp130 subeenheid Die beste bekend as 'n trombopoëtiese faktor
Stimuleer meerjarige stamvaders, eritropoïese, myelopoiese en limfopoiese
Verminder mukositis in dieremodelle
Stimuleer osteoklastontwikkeling
Inhibeer adipogenese
Stimuleer proliferasie van neuronale selle
IL-12 IL-12A:3p12-q13.2 IL-12Rβ1 en IL-12Rβ2 kettings is verwant aan gp 130 Pro-inflammatoriese sitokien belangrik in weerstand teen infeksies
IL-12B:5q31.1-q33.1 Th1 ontwikkeling
Stimulerende en inhiberende effekte op hematopoiese
IL-15 4q31 Hoë-affiniteit reseptor vereis IL-2Rβ en γ kettings en IL-15 Rα ketting Snellers proliferasie en immunoglobulienproduksie in vooraf geaktiveerde B-selle
Aantal CD8 + geheue T-selle kan beheer word deur balans van IL-15 (stimulerend) en IL-12 (inhiberend)
Stimuleer proliferasie van NK-selle en geaktiveerde CD4+ of CD8+ T-selle
Fasiliteer die induksie van LAK-selle en CTL's
Stimuleer mastselproliferasie
Bevorder die verspreiding van haarselleukemie en chroniese limfositiese leukemieselle
IL-16 15q26.1 Vereis CD4 vir biologiese aktiwiteite Tetraspanin CD9 Chemoattraktant vir CD4+-selle (T-selle, monosiete en eosinofiele)
Kan betrokke wees by asma en by granulomatiese inflammasie
Het antivirale effekte op MIV-1
IL-17 2q31 IL-17 reseptor Kan deels T-sel bydrae tot inflammasie bemiddel
Stimuleer epiteel-, endoteel-, fibroblastiese en makrofaagselle om 'n verskeidenheid inflammatoriese sitokiene uit te druk
Bevorder die kapasiteit van fibroblaste om hematopoietiese stamvadergroei te onderhou
Bevorder differensiasie van dendritiese selvoorlopers
Kan betrokke wees by die patogenese van rumatoïede artritis en entverwerping
IL-18 11q22.2-q22.3 IL-18 reseptor Bevorder produksie van IFN-γ en TNF
Teikens is T-selle, NK-selle en makrofage
Bevorder Th1-reaksies op virus
IL-19 1q32 IL-20Rl en IL-20R2 Induseer IL-6 en TNF-α
IL-20 1q32 IL-20R1 en IL-20R2 Induksie van gene betrokke by inflammasie soos TNF-α, MRP14 en MCP-1
IL-21 4q26–27 IL-21 reseptor Reguleer hoofsaaklik T-sel proliferasie en differensiasie
Reguleer sel-gemedieerde immuniteit en die opruiming van gewasse
IL-22 12q14 IL-22R1 en IL-10R2 Opreguleer die produksie van akute-fase reaktante
Induseer die produksie van ROS in rustende B-selle
IL-23 12q13 IL-12Rb1 en IL-23R 'n Unieke funksie van IL-23 is die voorkeur-induksie van proliferasie van die geheue subset van T-selle
IL-24 1q32 IL-20R1 en IL-20R2 Induseer IL-6, TNF-a, IL-1b, IL-12 en GM-CSF
IL-22R1 en IL-20R2 Funksioneel het dit teenoorgestelde effekte met IL-10
Infeksie met Ad-IL24 lei tot afregulering van Bcl-2 en Bcl-XL (antiapoptotiese proteïene) en opregulering van Bax en Bak (proapoptotiese proteïene) in kankerselle
IL-25 14q11 IL-17BR IL-25 induseer IL-4, IL-5 en IL-13 geenuitdrukking en proteïenproduksie
IL-26 12q14 IL-20R1 en IL-10R2 Immuniteit-beskermende rol teen virale infeksie
IL-27 12q13 TCCR/WSX-1 en GP130 Vroeë Th1 ontgroening
Sinergiseer met IL-12 in die indusering van IFN-γ-produksie deur T-selle en NK-selle
IL-28A, 28B en 29 19q13 IL-28R1 en IL-10R2 Antivirale aktiwiteite
IL-31 12q24 IL-31 reseptor A en onkostatien M reseptor Verantwoordelik vir die bevordering van die dermatitis en epiteelresponse wat allergiese en nie-allergiese siektes kenmerk
IL-32 16p13.3 Proteïenase 3 Induseer ander pro-inflammatoriese sitokiene en chemokiene soos TNF-α, IL-1β, IL-6 en IL-8
Induseer IκB degradasie
Fosforileer p38 MAPK seinweg
IL-33 9p24.1 ST2 Aktiveer NF-KB en MAP kinases
Bestuur produksie van Th2-geassosieerde sitokiene vanaf in vitro gepolariseerde Th2-selle
Induseer die uitdrukking van IL-4, IL-5 en IL-13
Lei tot ernstige patologiese veranderinge in slymvliesorgane
IL-35 19p13.3 IL-12Rβ2 en gp130 Dra Treg-onderdrukker aktiwiteit by
Induseer IL-10 en IFN-g serumvlakke
Verminder induksie van IL-17
IL-36 IL36A2q12-q14.1 IL-1Rrp2 en IL-1RAcP Aktiveer NF-KB en MAP kinases
IL36B2q14 Speel 'n belangrike rol in velbiologie
IL36G:2q12-q21 Betrokke by die aanvang en regulering van immuunresponse
IL36RN:2q14
IL-37 2q12-q14.1 IL-18R Reguleer inflammatoriese reaksies
IL-38 2q13 IL36R Verminder IL-36g-geïnduseerde IL-8-produksie

Die biologiese karakterisering van geselekteerde ILs (dié waarvoor ons 'n rol in kanker bespreek), interferone (IFNs) en geselekteerde groeifaktore, die rasionaal vir hul gebruik in terapie vir pasiënte met kanker, en die opgehoopte kliniese ervaring verteenwoordig die onderwerpe van hierdie hoofstuk .

Interleukiene

Interleukin-1

IL-1 (IL-1α en IL-1β) is die prototipiese pleiotropiese sitokien en beïnvloed byna elke seltipe. 1, 2 Omdat IL-1 'n hoogs inflammatoriese sitokien is, is die marge tussen heilsame effekte en ernstige toksisiteit by mense uiters smal. Verbindings wat die produksie en/of aktiwiteit van IL-1 verswak, word dus in kliniese proewe ondersoek.

Biologiese effekte van IL-1

IL-1 kan die uitdrukking van homself sowel as baie ander sitokiene (insluitend IL-1RA), sitokienreseptore (insluitend IL-2, IL-3, IL-5, granulosiet makrofaag-kolonie-stimulerende faktor [GM-CSF] verhoog) , en c-kit), inflammatoriese bemiddelaars (soos siklooksigenase en induseerbare stikstofoksiedsintase), hepatiese akute-fase reaktante, groeifaktore, stollingsfaktore, neuropaptiede, lipiedverwante gene, ekstrasellulêre matriksmolekules en onkogene (bv. jun, cabl, c-fms, c-myc en c-fos). 1 Data dui daarop dat 'n inflammatoriese komponent teenwoordig is in die mikro-omgewing van die meeste neoplastiese weefsels, insluitend dié wat nie oorsaaklik verband hou met 'n ooglopende inflammatoriese proses nie. Dus, as 'n pro-inflammatoriese sitokien, kan IL-1 ook 'n belangrike proangiogene stimulus van beide fisiologiese en patologiese angiogenese wees.

Die IL-1-familie is betrokke by die funksie en die disfunksie van feitlik elke menslike orgaanstelsel. Inderdaad, verhoogde IL-1-produksie is aangemeld by pasiënte met infeksies (virale, bakteriese, swam en parasitiese), intravaskulêre stolling, kanker (beide soliede gewasse en hematologiese maligniteite), Alzheimer se siekte, outo-immuunafwykings, trauma, iskemiese siektes , pankreatitis, ent-versus-gasheer siekte, oorplanting verwerping, en in gesonde vakke na oefening. 1

Daar is voorgestel dat die balans tussen IL-1 en sy natuurlik voorkomende antagoniste die meeste relevant is vir siekte. 3 Hierdie balans kan op verskillende maniere verander word, afhangende van die siekte. In AML word IL-10 spontaan uitgedruk, maar IL-1RA geenuitdrukking word onderdruk selfs wanneer dit met GM-CSF gestimuleer word. 4, 5 CML-pasiënte met gevorderde siekte en swak oorlewing het IL-1RA onderdruk, vergesel van hoë IL-1β. 6 In AML- en CML-pasiënte tree IL-1β op as 'n outokriene groeifaktor blootstelling aan molekules wat die aktiwiteit van IL-1 verminder, onderdruk leukemiese proliferasie. 7, 8 Konstitutiewe produksie van IL-la, IL-1β en/of IL-1RA in soliede gewasse (melanome, hepatoblastoom, sarkome, plaveiselkarsinome, oorgangsselkankers en eierstokkarsinome) is beskryf en kan in sommige gevalle, dra by tot metastatiese potensiaal. Die verhouding tussen IL-1 en tumorgroei is egter kompleks.

IL-1 in die kliniek

IL-la en IL-1β is albei in kliniese kankerproewe toegedien. 1 Oor die algemeen was die akute toksisiteite van beide isovorme groter na binneaarse as subkutane inspuiting. Subkutane inspuiting is geassosieer met beduidende plaaslike pyn, eriteem en swelling. Dosisverwante kouekoors en koors is in byna alle pasiënte waargeneem, en selfs 'n dosis van 1 ng/kg was pirogenies. Byna alle pasiënte wat binneaarse IL-1 teen dosisse van 100 ng/kg of meer ontvang het, het beduidende hipotensie ervaar, waarskynlik as gevolg van induksie van stikstofoksied.

IL-1-infusie in mense het sirkulerende IL-6-vlakke aansienlik verhoog en 'n toename in leukosiettellings tot gevolg gehad, selfs by dosisse so laag as 1 of 2 ng/kg. Toenames in bloedplaatjies, perifere monosiettelling en forbol-geïnduseerde superoksiedproduksie is ook waargeneem by pasiënte met normale murgreserwes. In teenstelling met die resultate by pasiënte met goeie murgfunksie, het pasiënte met aplastiese anemie wat met vyf daaglikse dosisse IL-la (30-100 ng/kg) behandel is, geen toename in perifere bloedtellings of beenmurgsellulariteit gehad nie. 9 Na chemoterapie het twee dosisse IL-10 egter die duur van neutropenie aansienlik verkort, 10 en IL-la (5 dae) het trombositopenie aansienlik verminder. 11 In die algemeen is die voordele van IL-1-terapie benadeel deur die toksisiteit daarvan.

Interleukin-2

Oorspronklik beskryf as 'n T-selgroeifaktor, strek die funksie van IL-2 verder as limfosietaktivering en bevolkingsuitbreiding, alhoewel T-selle steeds die hoofteiken daarvan blyk te wees. 12

Biologiese aktiwiteite van IL-2

IL-2 tree hoofsaaklik op as 'n T-selgroeifaktor, maar B-selle, natuurlike moordenaar (NK) selle en limfokien-geaktiveerde moordenaar (LAK) selle reageer ook op hierdie sitokien. Na binding van IL-2 met die trimeriese reseptorkompleks vind internalisering plaas en selsiklus progressie word geïnduseer in assosiasie met die uitdrukking van 'n gedefinieerde reeks gene. 13 'n Tweede funksionele respons vind plaas deur die IL-2β, dimeriese reseptor, ook bekend as die intermediêre affiniteit dimeriese kompleks (kDa, 10 −9), en behels die differensiasie van verskeie subklasse limfosiete in LAK selle. 14 Hierdie reaksie kom voor by pasiënte met kanker wat IL-2 15, 16 ontvang en is oorspronklik beskou as 'n kritieke deel van die teenkanker effek van IL-2.

IL-2 in die kliniek

IL-2 het 'n groot impak gehad op die ontwikkeling van kanker immunoterapie. Die toediening van IL-2 en die aanneemoordrag van antitumor T-selle wat in IL-2 gekweek is, verteenwoordig die eerste effektiewe immunoterapieë vir kanker by mense. 17 Sedert 1992 het talle kliniese proewe wat hoë dosis IL-2 (HD IL-2) gebruik het 'n merkwaardige konsekwente 7% volledige responskoers in twee gevorderde kankertipes, nierselkarsinoom (RCC) en kwaadaardige melanoom gelewer. 18–22 Baie van hierdie volledige antwoorde was langer as 10 jaar duur. HD IL-2 verhoog waarskynlik die immuunrespons teen kankerselle. Sy teenkankeraktiwiteit is sterk verwant aan sy vermoë om as 'n groeifaktor vir T-limfosiete op te tree, sy vermoë om antigeen-onafhanklike NK-selle en LAK-selle te stimuleer, en sy vermoë om limfosiete op die plek van kwaadaardigheid te verhoog. Die beduidende nadelige effekte van HD IL-2 is grootliks die gevolg van ernstige vasodilatasie en kapillêre lek sindroom, en sluit hipotensie, aritmieë en lewer- en niertoksisiteite in. Die toediening daarvan vereis 'n binnepasiënte intensiewe sorg-agtige omgewing, daarom word dit aanbeveel by pasiënte met min comorbiditeite en 'n uitstekende prestasiestatus. Daar is 'n 1-2% risiko van mortaliteit met IL-2, wat die belangrikheid van die keuse van 'n pasiënt wat goed geskik is vir hierdie behandelingsmodaliteit beklemtoon. 23

Histories is HD IL-2 vir die eerste keer gebruik in 'n kombinasie biochemoterapie (BCT) omgewing, wat gewoonlik cisplatien, vinblastien en dacarbazine (CVD) of cisplatin, vinblastien en temozolomied (CVT) behels, plus die biologiese middels IFN α en IL-2 . 'n Beskeie toename in oorlewing het egter gekom met 'n aansienlike toename in toksisiteit. 24 Meer onlangs, aangesien dwelms soos ipilimumab duursame reaksies toon, word die rol van HD IL-2 as 'n enkele middel meer kontroversieel. Een rasionele benadering is om die twee goedgekeurde immunoterapieë vir stadium IV melanoom, ipilimumab en IL-2 te kombineer. Geen data is tans beskikbaar rakende die korrekte volgordebepaling van immunoterapieë nie. Sommige melanoomkenners glo dat IL-2 die beste gebruik word baie vroeg in terapie wanneer proefpersone meer beperkte siekte (M1a-siekte) en goeie prestasiestatus het. 'n Klein studie het aangedui dat daar 'n hoër responskoers (47%) in pasiënte met NRAS-mutante melanoom kan wees, maar verdere validering van hierdie bevinding is nodig. 25 'n 2005-studie in 36 pasiënte met gevorderde melanoom wat 'n kombinasie van ipilimumab (0.1-3 mg/kg elke 3 weke) en IL-2 ontvang het, het 'n algehele responskoers van 22% getoon. 26 Studies wat die rol van ipilimumab met aanneemselterapie evalueer, is aan die gang. Nog 'n benadering om die doeltreffendheid van HD IL-2- of ipilimumab-terapie uit te brei of te verbeter, is om immunoterapie met BRAF-inhibeerders te kombineer vir die behandeling van pasiënte met BRAFV600-mutante gevorderde melanoom. 27 Prekliniese studies het 'n toename in melanoom-antigeenuitdrukking en die aantal tumor-infiltrerende limfosiete in tumorbiopsies na BRAF-inhibeerderterapie getoon, wat gekorreleer het met 'n vermindering in tumorgrootte en 'n toename in nekrose. 28, 29 Huidige pogings ondersoek tumorbiopsies van pasiënte wat vemurafenib ontvang om die meganismes en kinetika van T-sel-akkumulasie binne gewasse te assesseer en die spesifisiteit en funksie van immuuninfiltrerende selle te karakteriseer om meer suksesvolle kombinasiebehandelings van BRAF-inhibeerder- en immunoterapie-regimes te ontwerp.

Interleukin-3

IL-3 is die eerste keer beskryf as 'n T-selproduk betrokke by die patogenese van Moloney leukemievirus-geïnduseerde T-sel limfome. 30 Hierdie molekule is van belang as gevolg van sy vermoë om multilyn hematopoietiese stamvaders beide in vitro en in vivo te stimuleer. 30–37

Biologiese eienskappe van IL-3

In vitro veroorsaak IL-3, in kombinasie met ander sitokiene, soos stamselfaktor (SCF), IL-6, IL-1, GM-CSF, GM-CSF, eritropoïetien (EPO) of trombopoëtien (TPO), die proliferasie van kolonievormende eenheid (CFU)-GM, CFU-Eo, CFU-Baso, BFU-E en CFU-GEMM in halfvaste medium en stimuleer die proliferasie van gesuiwerde CD34+ selle in suspensiekultuur. 31 Inderdaad, IL-3 word gekombineer met ander sitokiene, veral SCF, IL-6, IL-1, FL, G-CSF (granulosiet kolonie-stimulerende faktor), en/of EPO, in byna alle protokolle om hematopoietiese stam uit te brei en stamvaderselle in vitro.

IL-3 in die kliniek

IL-3 is gebruik in 'n verskeidenheid van kliniese proewe perifere bloed stamsel mobilisering, postchemoterapie en oorplanting, en beenmurg mislukking state. Die meerderheid studies toon slegs beskeie effekte van IL-3 op sigself, maar beduidende heilsame effekte in samewerking met ander groeifaktore. Byvoorbeeld, in mobiliseringstudies, het behandeling met IL-3 nie op sigself gemobiliseer nie, maar aansienlik versterk G-CSF-geïnduseerde opbrengs van alle stamvader sel tipes wat gebruik word om hematopoïese te herstel na hoë dosis chemoterapie. Na oorplanting het die kombinasie van IL-3 en GM-CSF meer doeltreffend geblyk om beenmurg-inplanting te ondersteun as IL-3 of GM-CSF alleen. Die kombinasie van IL-3 en GM-CSF was meer doeltreffend as G-CSF vir die ondersteuning van bloedplaatjie herstel maar was van soortgelyke voordeel vir die hersamestelling van myelopoïese. Na chemoterapie is gevind dat IL-3 neutropenie en/of trombositopenie in sommige maar nie alle kliniese studies verminder nie.

Interleukien-4 en interleukien-13

IL-4 en IL-13 is nou verwant. 38–40 They share biologic and immunoregulatory functions on B cells, monocytes, dendritic cells, and fibroblasts. Both IL-4 and IL-13 genes are located in the same vicinity on chromosome 5. The major regulatory sequences in the IL-4 and IL-13 promoters are identical, thus explaining their restricted expression pattern in activated T cells and mast cells. Furthermore, the IL-4 and IL-13 receptors are multimeric and share at least one common chain—IL-4RA. This, together with similarities in IL-4 and IL-13 signal transduction, explains the striking overlap of biologic properties between these two cytokines. The inability of IL-13 to regulate T-cell differentiation due to a lack of IL-13 receptors on T lymphocytes, however, represents a major difference between these cytokines. Therefore, despite the impact redundancy of these two molecules, regulatory mechanisms are in place to guarantee their distinct functions.

Biologic activities of IL-4 and IL-13

IL-13 elicits many, but not all, of the biologic actions of IL-4. IL-4 is, however, distinguished from IL-13 by its T-cell growth factor activity and its ability to drive differentiation of Th0 precursors toward the Th2 lineage. Th2 cells secrete IL-4 and IL-5 and lead to a preferential stimulation of humoral immunity. In contrast, Th1 cells, which produce IL-2 and IFN-γ, lead to a preferential stimulation of cellular immunity.

IL-4 and IL-13 possess potent antitumor activity in vivo in mice. 41 They can inhibit the proliferation of some human cancer cell lines in vitro and in vivo in nude mice. A similar antiproliferative effect of IL-13 on human breast cancer cells has been described. Moreover, a chimeric protein composed of IL-13 and a truncated form of Pseudomonas exotoxin A exhibits specific cytotoxic activity toward human RCC but not against normal hemopoietic cells. 42

Clinical trials of IL-4

Despite the preclinical promise of IL-4, to date, clinical trials in humans demonstrated that although the molecule is safe and nontoxic, only sporadic antitumor activity is observed in a variety of cancers, including melanoma, lung cancer, and AIDS-related Kaposi’s sarcoma. 43–45

Interleukin-6

IL-6 was first cloned in 1986. 46 It is a typical cytokine, exhibiting functional pleiotropy and redundancy. IL-6 is involved in the immune response, inflammation, and hematopoiesis. IL-6 is a 21- to 30-kDa glycoprotein of 212 amino acids that binds to a specific receptor that requires the same 130-kDa membrane glycoprotein for mediation of signal transduction, as has been described for several cytokines, including IL-2. 47, 48

Biologic activities of IL-6

IL-6 affects the hypothalamic-pituitary axis, bone resorption, and both the humoral and cellular arms of the immune system 49–53 and is a potent and essential factor for the normal development and function of both B and T lymphocytes. 54 IL-6 is also involved in the differentiation of myeloid leukemic cell lines into macrophages, megakaryocyte maturation, neural differentiation, and osteoclast development. As a major inducer of acute-phase protein synthesis in hepatocytes, 55 this cytokine may play a role in the pathogenesis of sepsis.

IL-6 acts as a growth factor for myeloma/plasmacytoma, keratinocytes, mesangial cells, RCC, and Kaposi sarcoma and promotes the growth of hematopoietic stem cells. On the other hand, IL-6 inhibits the growth of myeloid leukemic cell lines and certain carcinoma cell lines. Significant correlations between serum IL-6 activity and serum levels of acute-phase proteins have been demonstrated in a variety of inflammatory conditions. IL-6 has been implicated as a mediator of B symptoms in lymphoma. 56 Elevated serum IL-6 levels have also been associated with an adverse prognosis in both Hodgkin lymphoma and non-Hodgkin lymphoma (NHL). 57–60 In diffuse large-cell lymphoma, IL-6 levels were found to be the single most important independent prognostic factor selected in multivariate analysis for predicting complete remission rate and relapse-free survival. 58 IL-6 levels may also be exploitable as a prognostic factor in RCC and multiple myeloma (MM), and high levels are observed in prostate and ovarian cancers. IL-6 probably also plays an etiologic role in the systemic manifestations of the lymphoproliferative disorder Castleman’s disease. 61 High IL-6 levels are also an adverse prognostic factor in pancreatic cancer. 62

IL-6 in the clinic

In patients undergoing chemotherapy or autologous transplantation, IL-6 has minimal to no platelet-enhancing activity at tolerable doses. Toxicity includes fever and anemia. 63–65 IL-6 has also been tested as an antitumor agent in melanoma and RCC. Response rates have been low (<15%). 55 Because high levels of IL-6 correlate with an adverse outcome in many cancers and function as an autocrine/paracrine growth factor in some tumors, clinical studies of an IL-6 inhibitor may be worthwhile.

IL-6 is one of the most ubiquitously deregulated cytokines in cancer, and increased levels of IL-6 have been observed in virtually every tumor studied. Preclinical and translational findings support a role for IL-6 in diverse malignancies, including breast, lung, colorectal, ovarian, prostate, pancreatic cancers, MM, glioma, melanoma, RCC, leukemia, lymphoma, and Castleman’s disease, and provide a biologic rationale for targeted therapeutic investigations. Various compounds antagonize IL-6 production, including corticosteroids, nonsteroidal anti-inflammatory agents, estrogens, and cytokines. Targeted biologic therapies include IL-6 conjugated toxins and monoclonal antibodies directed against IL-6 and its receptor. As an example, a chimeric murine antihuman IL-6 antibody, CNTO 328, has been used in a phase 1 trial in subjects with B-cell NHL, MM, and Castleman’s disease. 66 The treatment resulted in tumor response and disease control, especially in Castleman’s disease, where striking responses have been seen. 67

Interleukin-7

IL-7 was identified and cloned on the basis of its ability to induce proliferation of B-cell progenitors in the absence of stromal cells. 68–76 It is now known that this cytokine is secreted by stromal cells in the bone marrow and thymus and is irreplaceable in the development of both B and T cells. 69–71 Indeed, the nonredundant nature of IL-7 is underscored by the observation that ablation of IL-7 or parts of the IL-7 receptor in gene knockout mice ineluctably leads to a major defect in lymphocyte development.

Biologic activities of IL-7/IL-7 receptor

While most single cytokine knockout mice show relatively normal B- and T-cell compartments, indicating that many cytokine functions are redundant, IL-7-deficient mice present with striking lymphocyte depletion in both the thymus and bone marrow. Collectively, these genetic experiments identify clearly distinct in vivo roles for various lymphoid factors. IL-2 and IL-4 function by influencing mature lymphocyte populations during immune responses, whereas IL-7 plays a singularly dominant role for the production and expansion of lymphocytes. The upregulation of IL-7R occurs at the stage of the clonogenic common lymphoid progenitor that can give rise to all lymphoid lineages at a single-cell level. 74 There are at least three principal means by which IL-7R-mediated signals act in lymphocyte development: enhancement of proliferation, triggering of lineage-specific developmental programs, and maintenance of viability of appropriately selected cells.

High IL-7 levels are found in states of T-cell depletion and may, therefore, play a role in promoting T-cell expansion. 75 High levels of IL-7 are also found in CLL and Burkitt lymphoma, and transgenic mice overexpressing the IL-7 gene show dramatic changes in lymphocyte development, which, in some instances, can result in the formation of lymphoid tumors. 76

Interleukin-8

IL-8 was first identified in 1987 as a potent, proinflammatory chemokine that induces trafficking of neutrophils across the vascular wall (chemotaxis). 77 This molecule belongs to a chemokine superfamily whose members include neutrophil-activating peptide-2, platelet factor-4, growth-related cytokine (GRO), and IFN-inducible protein-10, all of which are responsible for the directional migration of various cells. 78 IL-8 receptor demonstrates strong homology to a gene encoded by human herpesvirus-8 (HHV-8). 79, 80

Biologic activity of IL-8

The chemotactic agents generated by inflammatory stimuli recruit circulating leukocytes, in particular neutrophils, for defensive purposes and direct them to injury sites. Among the neutrophil-affecting chemokines, IL-8 is one of the most potent. 81 On exposure to a chemokine, neutrophils are activated, and within seconds, their shapes change. The process of shape change is crucial. It is modulated by perturbations of cellular integrins and the actin cytoskeleton. The activation and upregulation of integrins also permits the adherence of neutrophils to the endothelial cells of the vessel wall, to allow for subsequent migration into the tissues. Leukocytes follow the IL-8 concentration gradient and accumulate at the location of elevated concentration. These processes play a fundamental role in the host defense as activated leukocytes act to kill and engulf invading bacteria at the site of injury.

IL-8 can induce tumor growth, an effect attributed to its angiogenic activity. On the one hand, the administration of anti-IL-8 to SCID mice bearing xenografts of IL-8-expressing human lung cancer has been shown to have beneficial effects. 82 On the other hand, antitumor effects of IL-8 have also been reported. Of interest in this regard is the fact that increased levels of IL-8 have been discerned in lung carcinomas and in melanomas. IL-8 may be a growth factor for pancreatic cancer and for melanoma. 78 In melanomas, IL-8 levels correlate with the growth and metastatic potential of the tumor cells, and exposure of the cells to IFN (an agent with known antitumor activity in melanoma) decreases IL-8 levels and cancer cell proliferation. 83 Blocking IL-8 or IL-8R has been suggested as a therapeutic strategy. 78

Interleukin-9

Human IL-9 was initially identified and cloned as a mitogenic factor for a human megakaryoblastic leukemia. Subsequently, IL-9 targets were found to encompass a wide range of cells. 84, 85

Biologic activities of IL-9

Cellular elements responsive to IL-9 include erythroid progenitors, human T cells, B cells, fetal thymocytes, thymic lymphomas, and immature neuronal cell lines. 84

IL-9 can support the clonogenic maturation of erythroid progenitors in the presence of EPO. In contrast, granulocyte or macrophage colony formation (CFU-GM, CFU-G, or CFU-M) is usually not influenced by IL-9. IL-9 is more effective on fetal than adult progenitors and in cells that are activated. In addition to its proliferative activity, IL-9 also seems to be a potent regulator of mast cell effector molecules.

There is an interesting paradox between the unresponsiveness of normal T cells to IL-9 and the potent activity of this molecule on lymphoma cells. This contrast is illustrated by the observation that murine T cells acquire the ability to respond to IL-9 after a long period of in vitro culture, while they simultaneously acquire characteristics of tumor cell lines. Observations made with transgenic mice also demonstrate the oncogenic potential of dysregulated IL-9 production as 5–10% of mice that overexpress this cytokine develop lymphoblastic lymphomas. 85 In line with these data, constitutive IL-9 production by human Hodgkin lymphomas and large-cell anaplastic lymphomas has now been clearly documented. 84 Even so, the pathophysiologic role of IL-9 remains elusive.

Interleukin-10

IL-10 is a pleiotropic cytokine discovered in 1989 as an activity produced by murine type 2 helper T cells (Th2). 86, 87 It was initially designated as cytokine synthesis inhibitory factor because of its ability to inhibit the production of certain cytokines. 88 Of interest, IL-10 exhibits strong DNA and amino acid sequence homology to an open reading frame—BCRF1—in the Epstein–Barr virus (EBV) genome. 88 Indeed, the BCRF1 protein product displays many of the biologic properties of cellular IL-10 and has, therefore, been termed viral IL-10.

Biologic activities of IL-10

IL-10 inhibits the synthesis of Th1-derived cytokines, including IL-2, IFN-γ, GM-CSF, and lymphotoxin and of monocyte-derived IL-1α and β, IL-6, IL-8, TNF-α, GM-CSF, and G-CSF. Exogenous IL-10 can also suppress expression of IL-10. 87 At the same time, IL-10 induces the synthesis of the IL-1 receptor antagonist by macrophages. IL-10 also suppresses the CD28 costimulatory pathway and hence acts as a decisive mechanism in determining if a T cell will contribute to an immune response or become anergic.

From the molecular standpoint, IL-10 suppresses cytokine expression at a transcriptional and posttranscriptional level. 89 Both these mechanisms appear to require new protein synthesis. At a cellular level, Th1 cytokines synthesis inhibition is mediated indirectly through the effect of IL-10 on APC, as suppression occurs when macrophages, but not B cells, are used as APC. 90

In the presence of monocytes/macrophages, IL-10 inhibits proliferation of resting T cells, including Th0, Th1, and Th2 CD4+ T-cell clones. This inhibition can only be partially reversed by high concentrations of IL-2, suggesting that the reduced proliferation is only partially a reflection of reduced IL-2 production. IL-10 can also enhance the cytotoxic activity of CD8+ T cells. All these effects support an important role of IL-10 in regulating inflammatory responses. In contrast to the inhibitory effects on other lineages, IL-10 has a stimulatory effect on B cells and mast cells. 91 For instance, IL-10 strongly stimulates proliferation and differentiation of activated B cells.

The role of IL-10 in cancer should be considered within the frame of a highly complex biological puzzle. It is known that IL-10 can have pleiotropic effects on adaptive and innate immunity cell mediators. Although several studies show that IL-10 can actively mediate immune suppression, some experimental models describe relatively opposite conclusions. Recent data on the relationship between IL-10 and anticancer immunity support an effective immune attack against malignant cells, which challenges the common belief that IL-10 acts as an immunosuppressive factor promoting tumor immune escape.

Interleukin-11

Originally characterized as a thrombopoietic factor, IL-11 is now known to be expressed and have activity in a multitude of other systems, including the gut, testes, and the central nervous system. 92, 93 Clinically, this cytokine has been approved by the FDA for amelioration of chemotherapy-induced thrombocytopenia.


2. The Glioblastoma TME

In common with other solid tumours, the glioblastoma microenvironment harbours an array of non-malignant (stromal) cell types in addition to the cancer cells themselves [18,19]. The main stromal cell types in glioblastoma are cells of the immune system𠅍iscussed in detail below𠅊nd cells associated with the structure and function of blood vessels (endothelial cells and pericytes) [20]. In contrast to most other tumour types, fibroblasts are not known to be a significant component of the glioblastoma TME. Vessels promote the growth and survival of glioblastoma cells, by facilitating blood perfusion and hence the provision of essential oxygen and nutrients. In addition, the perivascular zone can serve as a specialised niche to support the survival and function of glioma stem cells (GSCs), which are self-renewing, multipotent cells thought to produce the bulk of the malignant cells in glioblastoma [21]. In contrast, the role of immune cell populations is more complex, and the balance of pro-tumour versus anti-tumour populations likely plays a critical role in determining the trajectory of tumour growth and spread.

For many years, the brain was viewed as an immune privileged site, protected from the regular surveillance systems that operate in the periphery [22]. This concept was supported by a perceived lack of lymphatic vessels in the brain, thereby separating the brain from central lymphocyte circulation pathways, and the presence of the blood𠄻rain barrier (BBB), which restricts the entry of leukocytes from the blood. However, functional lymphatic vessels have recently been discovered to line the dural sinuses of mice, and potentially analogous structures exist in human dura [23], suggesting that the brain is not in fact immunologically separate from the periphery. In addition, the BBB is frequently compromised in glioblastoma [22], and priming of tumour-specific T cells has been detected in glioblastoma patients [16]. Thus, it is clear that glioblastoma tumours interact with the immune system, but immune-mediated tumour control is likely hampered by an overwhelmingly immunosuppressive TME.

Cells of the myeloid lineage are a major component of the glioblastoma TME [20,24,25,26]. In fact, these cells are reported to constitute a remarkable 30�% of the glioblastoma tumour mass. Myeloid cell types within the glioblastoma TME include brain-resident microglia and infiltrating macrophages, which are collectively referred to as glioma-associated microglia and macrophages (GAMs), as well as myeloid-derived suppressor cells (MDSCs). Microglia are derived from primitive yolk sac progenitors that enter the brain during embryogenesis and reside as a local resident population throughout life [25,26]. They play many critical roles under conditions of homeostasis, including synaptic pruning and the regulation of sleep and memory, as well as serving as local sensors of neuronal damage and infection. In contrast, infiltrating macrophages are thought to enter the tumour as blood-borne monocytes, which are recruited in response to inflammatory stimuli, and then differentiate to macrophages once they enter the TME [19,25]. Finally, MDSCs are immature myeloid lineage cells with inherent immunosuppressive properties [19,27]. They arise through a pathological (tumour-driven) block in normal myeloid differentiation pathways, leading to the accumulation of an abnormal population of partially differentiated myeloid cells. MDSCs exploit a number of immunosuppressive mechanisms to inhibit adaptive immune responses, including the depletion of nutrients required for effective T cell responses, the generation of oxidative stress conditions that inhibit T cell function, and the activation and expansion of regulatory T cells (Tregs) [19,27].

In contrast to the inherent immunosuppressive properties of MDSCs, macrophages and microglia are more plastic cell types that can be readily polarised according to their local environment, resulting in highly divergent functions [19,25,27]. According to the M1/M2 paradigm, 𠆌lassically activated’ macrophages (M1) assume an inflammatory phenotype characterised by efficient phagocytosis and antigen presentation, and abundant production of pro-inflammatory cytokines. In contrast, 𠆊lternatively activated’ macrophages (M2) largely produce anti-inflammatory cytokines and support tissue remodelling and matrix deposition. However, this proposed dichotomy is largely based on in vitro studies, and it is likely that macrophages in tissues rarely exist in such clearly defined states. Indeed, although GAMs clearly can express markers of the immunosuppressive M2 phenotype, including TGF-β, IL-10, CD163 and CD204, unbiased transcriptomic analyses characterised GAMs in patient tissues as more in keeping with a non-polarised M0 phenotype [28], or a mixed M1/M2 phenotype [29].

GAMs are most commonly considered to have a pro-tumorigenic function. For example, they possess multiple immunosuppressive properties, secrete factors that actively promote tumour cell proliferation and invasion, and in certain animal models it has been demonstrated that depletion of GAMs can significantly reduce tumour growth [19,25,26,30,31]. Furthermore, in patient glioblastoma tissues, the proportion of M2 macrophages is reported to positively correlate with the rate of tumour cell proliferation [32]. However, several other studies have shown conflicting results. For example, in some animal models GAM depletion actually enhances tumour growth [25,33], while a high frequency of either total or M2-phenotype GAMs in patient glioblastoma tissues correlate with improved survival [29]. The role of GAMs in the growth and progression of glioblastomas is therefore likely to be complex and highly context-dependent and requires further study.

Although GAMs represent the predominant immune cell population in glioblastoma, significant populations of lymphocytes are also present. These are primarily T cells, although natural killer (NK) cells and B cells have also been identified in human glioblastomas, the latter being relatively rare [19]. The T cell population in glioblastoma generally displays a profoundly exhausted phenotype, characterised by expression of LAG3, TIGIT, CD39 and especially programmed cell death 1 (PD1) [34]. T cell anti-tumour activity can also be inhibited by indoleamine 2,3-dioxygenase (IDO), an enzyme present in the TME responsible for catalysing the oxidation of tryptophan to downstream metabolites belonging to the kynurenine pathway. This can, through a variety of mechanisms, lead to T cell dysfunction, an effect that is particularly pronounced in the setting of advanced age [35,36]. Furthermore, Tregs are enriched in glioblastoma lesions compared to peripheral blood, and are expected to further inhibit the function of effector T cells, as well as NK cells [19,37]. This severely immunosuppressed microenvironment likely contributes to the apparent inability of infiltrating T cells to control tumour growth. This effect is compounded by the inherent low immunogenicity of glioblastoma tumours, which generally lack the high mutation rate thought to be required for robust anti-tumour T cell responses [38]. However, it is worth noting that a high effector CD8+ T cell frequency in patient glioblastoma tissues is associated with prolonged survival [39]. In addition, ICI therapies, which promote anti-tumour T cell responses, can induce regression of glioblastomas harbouring germline mismatch repair deficiency, which are characterised by a greatly elevated mutation rate [12]. Thus T cells may have the potential to control glioblastoma growth in circumstances where their frequency and function are optimal, highlighting the therapeutic potential of T cell-based therapies in this disease.


Interferon Types

Interferons are currently classified into three groups: type I, type II and type III IFNs. The type I IFNs include all IFNαs, IFNβ, IFNε, IFNκ, IFNω and IFNν. Humans have 12 different IFNαs and a single IFNβ. Type I IFN genes are clustered on the human chromosome 9. Each subtype is encoded by its own gene and regulated by its own promoter, and none of them contain introns. The different IFNαs and IFNβ differ substantially in their specific antiviral activities and in the ratios of antiviral to antiproliferative activities. However, the molecular basis of these differences is not yet known. All type I IFNs bind to the same interferon alpha/beta receptor (IFNAR) which consists of two major subunits: IFNAR1 and IFNAR2c (the βL subunit).

There is only one class II IFN, IFNγ. Interferon gamma is produced by T lymphocytes when stimulated with antigens or mitogens. IFNγ binds to a distinct receptor, the interferon gamma receptor (IFNGR) consisting of the two subunits IFNGR1 (previously α chain) and IFNGR2 (previously β chain or accessory factor).

The more recently described type III IFNs IFNλ2, IFNλ3 and IFNλ1 are also known as IL28A, IL28B and IL29 respectively. The same as type I IFNs, they are also induced by viral infections. They signal through the IFN-λ receptor consisting of the IL-10R2 chain shared with the IL-10 receptor, and a unique IFNλ chain.


Role of Chemokines in Neutrophil Heterogeneity

Despite the previous belief that differentiated neutrophils were a homogeneous population, the existence of different circulating subsets was demonstrated in varied health and disease contexts, both in mice and humans (51) (Figure 1). A consensus on the phenotype of these subpopulations is still missing and under steady-state conditions heterogeneity may arise mainly from the aging process of circulating neutrophils (52). Indeed, neutrophils oscillate in a circadian manner in numbers, morphology, and phenotype (53, 54). This process is regulated by gut microbiota (55) and is controlled by neutrophils themselves through the circadian expression of the transcription factor Bmal1 that controls the production of CXCL2. In turn, CXCL2 acting on CXCR2 induces neutrophil aging (56).

During inflammatory conditions, increased levels of a neutrophil circulating population that shared characteristics with BM immature neutrophils was described both in mice and humans. These cells express low levels of CD16 and are CD10 − (57�). The functional properties of this subset are still controversial, they were described having either immunosuppressive activity (60) or promoting T-cell survival and proliferation (57).

Other circulating neutrophils subpopulations were described: olfactomedin 4 (OLFM4)-positive neutrophils in healthy donors (61), T-cell receptor (TCR)�sed variable immunoreceptor neutrophils (62), and CD177 + neutrophils during inflammatory diseases both in mice (63) and humans (64).

In addition, a reverse transendothelial migrating neutrophil subset (rTEM) was described in a murine model of sterile injury (65). These neutrophils are CD54 hi and, in order to reverse transmigrate into vasculature, downregulate CXCR1. Concomitantly, they upregulate CXCR4 to go into the lungs, before being cleared in BM (66). This subset represents a phenotypically and functionally distinct population different from circulating neutrophils (CD54 lo CXCR1 hi ) and express vascular endothelial growth factor receptor (VEGFR) 1, indicating a possible role in angiogenesis (67, 68). Similar cells, with increased levels of CD54 and CD18 and downregulation of CD62L and CXCR1 and 2, were found in patients with chronic inflammatory diseases, suggesting a role of rTME neutrophils in the persistence of inflammation (67). Moreover, around 1% of circulating neutrophils after ischemia-reperfusion were found to be CD54 hi and producing ROS into lungs (65). On the contrary, neutrophils that migrate away from the inflammation site in interstitial tissues are called reverse interstitial migration (rIM) neutrophils and are supposed to contribute to the resolution of inflammation. The role of chemokine receptors in this process is still not clear (69).

Finally, in circulation it is possible to identify aged or senescent neutrophils (54, 70, 71). Ex vivo aging experiments have shown that neutrophils kept in culture downregulate the expression of CXCR2 (44) and re-express CXCR4 in a time-dependent way (22), suggesting a preferentially homing of senescent cells to the BM in response to CXCL12 (21). In mice aged neutrophils display circadian oscillations and, in addition to high levels of CXCR4, are characterized by an increased surface expression of CCR5 and decreased expression of CD62L (53, 72). CXCR4 upregulation seems involved not only in guiding neutrophils back to the BM but also in their migration within the marrow tissue in order to be engulfed with greater efficacy by macrophages (17, 19, 53, 54, 72). CCR5 was reported to work as a chemokine scavenger promoting the resolution of the inflammatory response (73). Aged neutrophils were found in lungs, where pulmonary vasculature expresses CXCL12, and this could either supply the pool of circulating neutrophils or respond to injury (45, 68).

New data from single cell sequencing of murine circulating neutrophils confirm the presence of three transcriptionally different neutrophil subpopulations. The first expresses high levels of inflammatory genes and the highest levels of CXCR2 arising mainly from BM mature neutrophils. The second expresses interferon-stimulated genes and derives from BM immature neutrophils. Both populations mature in an aged subset CXCR4 positive with high phagocytic activity and still highly transcriptionally functional (41). The correlation of these subpopulations of neutrophils with the others described in the foregoing is still missing. In addition, the role of chemokines in the mobilization and function of these neutrophil subpopulations is not known. Of relevance, at least in mice, mobilization of immature neutrophils could be CXCR2 independent because they are referred to as CXCR2 negative (44).

Finally, neutrophil heterogeneity has been described in tumors where tumor-associated neutrophils (TANs) can exist in two different functional states: N1 proinflammatory and antitumoral subset and an antiinflammatory tumor promoting N2 population, distinguished for the expression of adhesion molecules, cytokines and inflammatory mediators, chemokines, and chemokine receptors (4, 74). N1 phenotype has been associated with IFN-β polarization both in mice and humans. These cells have an activated phenotype (CD62L lo CD54 + ) express the chemokine receptors CCR5, CCR7, CXCR3, and CXCR4 and produce the proinflammatory chemokines and cytokines: CCL2, CXCL8, CCL3, and interleukin-6 (IL-6). Moreover, this subset has been associated with stimulation of T-cell responses and ROS production (4, 75, 76). In contrast, N2 neutrophils are induced by transforming growth factor- β (TGF-β) stimulation. Protumoral N2 neutrophils display high levels of CXCR4, VEGF, and matrix metalloproteinase 9 (MMP-9) (77), and produce high levels of CCL2, CCL5, neutrophil elastase (NE), cathepsin G (CG), and arginase 1 (78�).

Therefore, results obtained in preclinical mouse models and in humans suggest that the interplay between CXCR2 and CXCR4 dictates not only BM neutrophil mobilization and retention but also neutrophil diversity in homeostasis. CXCR2 signaling promotes neutrophil aging and CXCR4 guides their homing back to the BM. Furthermore, diversity of tissue infiltrating neutrophils is also associated with a distinct pattern of chemokine receptors in particular N1 neutrophils express inflammatory CC chemokine receptors important for their effector functions (see later).


Diagnostic value of cytokines and chemokines in lyme neuroborreliosis

The aims of the present study were to assess the concentrations of different cytokines and chemokines in blood serum and cerebrospinal fluid (CSF) samples of patients with Lyme neuroborreliosis and to identify the possible marker(s) that would enable a distinction between clinically evident and suspected Lyme neuroborreliosis, as well as between Lyme neuroborreliosis and tick-borne encephalitis (TBE). Our additional interest was to evaluate the relationship between cytokine and chemokine concentrations and Borrelia burgdorferi sensu lato isolation from CSF, as well as intrathecal synthesis of specific borrelial antibodies. We found that higher concentrations of CXCL13 and lower concentrations of interleukin 10 (IL-10) in serum were associated with higher odds for clinically evident Lyme neuroborreliosis compared to suspected Lyme neuroborreliosis, as well as to TBE. The concentrations of IL-2, IL-5, IL-6, IL-10, and CXCL13 in the CSF were higher in patients with evident Lyme neuroborreliosis than in those who were only suspected to have the disease. A comparison of CSF cytokine and chemokine levels in patients with and without intrathecal synthesis of specific borrelial antibodies revealed that CXCL13 CSF concentration is significantly associated with intrathecal synthesis of borrelial antibodies. A comparison of the cytokine and chemokine CSF concentrations in patients with clinically evident Lyme neuroborreliosis according to CSF culture results revealed that higher concentrations of gamma interferon (IFN-γ) were associated with lower odds of Borrelia isolation. Although several differences in the blood serum and CSF concentrations of various cytokines and chemokines between the groups were found, the distinctive power of the majority of these findings is low. Further research on well-defined groups of patients is needed to appraise the potential diagnostic usefulness of these concentrations.

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CONCLUSIONS

IL-36α, IL-36β, and IL-36γ signal through the same receptor and appear to have the identical effects on cells and in vivo, which calls into question the need for 3 ligands. There is evidence that the expression patterns for IL-36 ligands are different, with IL-36γ as the most highly expressed and inducible in skin and lung. In addition, there is very little sequence homology among the 3 ligands around the site of cleavage, suggesting differential mechanisms for producing the active form. Therefore, whereas all IL-36 ligands appear to have the same activity, their expression and activation are likely differentially regulated. More work needs to be done to address the regulation of IL-36 cytokines at the expression level, as well as to define and understand the forces governing their truncation. Whereas it is clear that processing these ligands must occur for their activity, the identity of the enzymes involved in the regulation of this process is unknown. Demonstration that truncation of IL-36 ligands occurs in vivo and under certain circumstances and the search for the proteases involved are active areas of research.

Recent data have emerged demonstrating that IL-36 cytokines play a crucial role in the skin, most dramatically evidenced by the genetic variants in IL36RN, leading to the life-threatening disease GPP, the marked up-regulation of IL-36 cytokines in psoriatic lesional tissue, and the ability of IL-36R neutralization to decrease the inflammation and skin thickening of human psoriatic tissue when engrafted onto mice. Despite convincing evidence for a role for these cytokines in skin pathology and the strong ability to induce inflammatory responses in the lung, it is not yet clear whether IL-36 plays a role in pathologic conditions in the lung, such as asthma or COPD, and whereas IL-36 cytokines are expressed in other tissues, including the kidney, brain, and gut, it is unclear what role they play in the physiology or pathophysiology of these tissues. In addition, whereas IL-36 clearly acts on DCs to enhance their maturation and production of cytokines and acts on nai¨ve T cells in mice, the full role of these cytokines on human immune cells is not yet clear. Can IL-36 act on human αβ T cells or γδ T cells if provided in the right context? Likewise, the role of IL-36 on macrophages, in particular, of different subtypes and activation states has not been thoroughly explored. Similar to its fellow family members—IL-1, IL-18, and IL-33—IL-36 likely plays a prominent role in human health, and further studies assessing the expression and activity of IL-36 in the context of disease will likely uncover additional roles for these cytokines.


Interleukins

Interleukins are a group of cytokines that act as chemical signals between white blood cells. Interleukin-2 (IL-2) helps immune system cells grow and divide more quickly. A man-made version of IL-2 is approved to treat advanced kidney cancer and metastatic melanoma. IL-2 can be used as a single drug treatment for these cancers, or it can be combined with chemotherapy or with other cytokines such as interferon-alfa.

Side effects of IL-2 can include flu-like symptoms such as chills, fever, fatigue, and confusion. Some have nausea, vomiting, or diarrhea. Many people develop low blood pressure, which can be treated with other medicines. Rare but potentially serious side effects include an abnormal heartbeat, chest pain, and other heart problems. Because of these possible side effects, if IL-2 is given in high doses, it must be done in a hospital.

Other interleukins, such as IL-7, IL-12, and IL-21, continue to be studied for use against cancer too, both as adjuvants and as stand-alone agents.


FINAL REMARKS

The chemokine/cytokine network is profoundly involved in the control of HIV infection as it is both a main target of the HIV-induced dysregulation and, at the same time, a complex modulator of the susceptibility of immune cells to infection and replication. The recent findings that chemokines can affect binding, entry, and post-entry events, and that cytokines can influence HIV infection by modulating the expression of chemokines and their receptors as well as the extent of viral replication, further support the general model that multiple steps of the life cycle of HIV are regulated by this network (Table 2and 3). Macrophages serve as a major reservoir and vehicle for dissemination of HIV in different tissues. Thus, HIV harbored in these cells may escape immune surveillance and antiviral therapy. Although highly active antiretroviral therapy (HAART) significantly suppresses viral replication, ongoing viral replication and spreading has been observed during HAART, especially in macrophages with respect to resting T cells [59 ]. Therefore, macrophages can play a key role in regulating the intensity and progression of HIV disease even during therapy, and their secretory products have been implicated in the pathogenesis of AIDS [234, 10, 11 ]. In conclusion, exploitation of knowledge on the interactions between HIV and macrophages in their milieu of cytokines and chemokines may lead to novel and more effective strategies of preventive or therapeutic interventions. Unraveling this complex network of interactions is of relevance for the eradication of tissue viral reservoirs of long-lived, latently infected cells, as well as for the development of molecules capable of interfering with HIV entry by targeting chemokine receptors.


Kyk die video: Cytokines - IL-2, IL-3, Interferon-gamma, IL-4, IL-5, IL-10 - Secreted by T Cells (September 2022).


Kommentaar:

  1. Brone

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  2. Chet

    dit is die spesiale geval.

  3. JoJoktilar

    Dit is die snaakse antwoord



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