Abstract
The proinflammatory cytokine interleukin (IL)-18 is an important mediator of the organ failure induced by endotoxemia. IL-18 (known as an interferon-gamma (IFN-γ) inducing factor), and other inflammatory cytokines have important roles in lipopolysaccharide (LPS)-induced acute kidney injury (AKI). We investigated the effect of inflammatory cytokines and Toll-like receptor 4 (TLR4) expression, an event that is accompanied by an influx of monocytes, including CD4+ T cells and antigen-presenting cells (APCs) in IL-18Rα knockout (KO) mice and wild-type (WT) mice after LPS injection. In the acute advanced phase, the IL-18Rα KO mice showed a higher survival rate and a suppressed increase of blood urea nitrogen, increased levels of proinflammatory cytokines such as IFN-γ and IL-18, the infiltration of CD4+ T cells and the expression of kidney injury molecule-1 as an AKI marker. In that phase, the renal mRNA expression of the M1 macrophage phenotype and C-C chemokine receptor type 7 as the maturation marker of dendritic cells (DCs) was also significantly decreased in the IL-18Rα KO mice, although there were small numbers of F4/80+ cells and DCs in the kidney. Conversely, there were no significant differences in the expressions of mRNA and protein TLR4 after LPS injection between the WT and IL-18Rα KO groups. Our results demonstrated that the IL-18Rα-mediated signaling pathway plays critical roles in CD4+ T cells and APCs and responded more quickly to IFN-γ and IL-18 than TLR4 stimulation in the pathogenesis of LPS-induced AKI.
Highlights
Interleukin (IL)-18 is a proinflammatory cytokine produced by antigen-presenting cells (APCs) and T cells such as macrophages, dendritic cells (DCs) and CD4+ T cells
It was demonstrated that IL-18 is an interferon-gamma (IFN)-γ- and tumor necrosis factor (TNF)-inducing factor based on to its ability to induce the production of TNF and IFN-γ in APCs, T cells and monocytes [8]
We investigated the effects of inflammatory cytokines and Toll-like receptor 4 (TLR4) expression in IL-18Rα-deficient mice after LPS injection, and we observed that the survival rate and renal function were improved by suppressing serum inflammatory cytokines and the renal cytokine mRNA expressions and an accumulation of CD4+ T cells in IL-18Rα KO mice
Summary
Interleukin (IL)-18 is a proinflammatory cytokine produced by antigen-presenting cells (APCs) and T cells such as macrophages, dendritic cells (DCs) and CD4+ T cells. It was demonstrated that IL-18 is an interferon-gamma (IFN)-γ- and tumor necrosis factor (TNF)-inducing factor based on to its ability to induce the production of TNF and IFN-γ in APCs, T cells and monocytes [8]. We hypothesized that if an injured kidney becomes hyper-responsive to lipopolysaccharide (LPS), which is a component of Gram-negative bacteria, it may pInrt.oJd. Mucotl.ioScni. We hypothesized that if an inj2uorfe1d6 kidney becomes hyper-responsive to lipopolysaccharide (LPS), which is a component of Gram-negative bacteria, it may increase the levels of circulating inflammatory cytokines such as TinNcrFeaasnedtIhFeNl-eγvaenlsdorfescuirlctuinlaatinwgorinseflnaimngmoaftothrey AcyKtIo,krienseusltisnugchinafsurTtNheFr adnadmaIFgNe t-oγ raenndalrfeusnuclttioinn.a worsTenhiengreopfotrhteedAKinI,crideseunlcteingofinAfKurIthrearndgeasmfargoemto5r%enainl fuanllcthioons.pitalized patients to 30–50% in intenTsihveerceaproerutenditisn[c9id].eInncfeiltorfaAtinKgI craenllgs ehsafvreombe5e%n iinndailclahteodsptiotaplilzaeydimpaptoierntatsnttoro3l0e–s5i0n%thine iinnitteinatsiiovne acanrde upnroitgsr[e9s]s. InTfhlaemremnaatlosrtyatucsytoofktihneesILa-f1t8eRr αLKPSO imnjieccetiwona.s aTlhsoe eaxmperleiossriaotneds boyf mthRe NdoAwannredgpurlaottieoinn oTfoilnl-fllaikmemreacteoprytocry4to(kTinLeRs4a)ftienr ILLP-1S8iRnαjecKtiOon.mTihcee edxidprnesostiodnifsfeorf smigRnNifAicaanntdlyprboettewineeTnollb-leifkoerreecaenpdtoarf4te(rTLthRe4y) iwneILre-1i8nRjeαctKedO mwiicthe dLiPdSn.oOt duirffreerssuigltnsifiincdanictalytebethtwateeinn tbheefoLrPeSa-ninddauftceerdthAeKyIwmeoredeinl jmecitceed, IwL-it1h8RLαPSh.aOsuarcrreuscuialtlsainnddidcairteectthsaigt ninaltihnegLpPaSth-iwndauyciendCADK4I+ Tmcoedlelsl imniAceP, CILs-1a8nRdαnohtasviaacaruTcLiaRl4asnidgndailriencgt spiagtnhawlinayg.pathway in CD4+ T cells in APCs and not via a TLR4 signaling pathway Ionffitlutrbautilnegdcyesllfsuhnacvtieobneaenndinsdtircuactteudratol pinlajuyriymipnoArtKanIt[r1o0l]esbiyn itnhheiibniittiinagtioinnfailntrdaptiroongsrebsys loyfmtupbhuolceydteyssfu[1n1c]tioonr amndacsrtorpuhctaugreasl i[n1j2u]r,ylienadAiKngI [1to0] dbyecirnehaisbeidtintgubinufileltrdataimonasgbey. lIynmtphheocreypteasir[1o1f] eopr imthaeclriaolpchealglsetsh[a1t2]o,clceuardsining rtoesdpeocnrseeasteodatnubAuKleI,dthame dagifefe. rIenntthiaetrioenp,aimr iogfreaptiiothnealinadl cperlloslitfhearat toioccnuorsf sinurrveisvpionngsteubtoulaanr AceKllsI,itsheessdeinffteiarelnfotiratthioenr,emstoigrraatitoionnoafntidsspureoilnifteergartiitoyn[1o3f,s1u4]r.viving tubular cells is essenWtiael dfoermthoensrtersattoerahteioreninoftthiasstuwehinetnegILri-t1y8[R1α3,1k4n]o. ckout (KO) mice experienced an LPS-induced AKI,Wtheedyehmaodnmstraartkeehdelyreianmthelaitorwahteedn rILen-1a8lRfαunkcntioocnk.oTuht e(KrOen)aml iscteateuxspeorfiethneceIdL-a1n8LRPαSK-inOdumciecde AwKaIs, athlseoy haamdelmioarrakteeddlybyamtehleiordaotwednrreegnuallaftuionnctioofn. inTfhlaemremnaatlosrtyatucsytoofktihneesILa-f1t8eRr αLKPSO imnjieccetiwona.s aTlhsoe eaxmperleiossriaotneds boyf mthRe NdoAwannredgpurlaottieoinn oTfoilnl-fllaikmemreacteoprytocry4to(kTinLeRs4a)ftienr ILLP-1S8iRnαjecKtiOon.mTihcee edxidprnesostiodnifsfeorf smigRnNifAicaanntdlyprboettewineeTnollb-leifkoerreecaenpdtoarf4te(rTLthRe4y) iwneILre-1i8nRjeαctKedO mwiicthe dLiPdSn.oOt duirffreerssuigltnsifiincdanictalytebethtwateeinn tbheefoLrPeSa-ninddauftceerdthAeKyIwmeoredeinl jmecitceed, IwL-it1h8RLαPSh.aOsuarcrreuscuialtlsainnddidcairteectthsaigt ninaltihnegLpPaSth-iwndauyciendCADK4I+ Tmcoedlelsl imniAceP, CILs-1a8nRdαnohtasviaacaruTcLiaRl4asnidgndailriencgt spiagtnhawlinayg.pathway in CD4+ T cells in APCs and not via a TLR4 signaling pathway
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