Abstract
PIM kinases, a small family of serine/threonine kinases, are important intermediates in the cytokine signaling pathway of inflammatory disease. In this study, we investigated whether the novel PIM kinase inhibitor KMU-470, a derivative of indolin-2-one, inhibits lipopolysaccharide (LPS)-induced inflammatory responses in RAW 264.7 cells. We demonstrated that KMU-470 suppressed the production of nitric oxide and inducible nitric oxide synthases that are induced by LPS in RAW 264.7 cells. Furthermore, KMU-470 inhibited LPS-induced up-regulation of TLR4 and MyD88, as well as the phosphorylation of IκB kinase and NF-κB in RAW 264.7 cells. Additionally, KMU-470 suppressed LPS-induced up-regulation at the transcriptional level of various pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-6. Notably, KMU-470 inhibited LPS-induced up-regulation of a major component of the inflammasome complex, NLRP3, in RAW 264.7 cells. Importantly, PIM-1 siRNA transfection attenuated up-regulation of NLRP3 and pro-IL-1β in LPS-treated RAW 264.7 cells. Taken together, these findings indicate that PIM-1 plays a key role in inflammatory signaling and that KMU-470 is a potential anti-inflammatory agent.
Highlights
PIM kinases are a family of serine/threonine kinases that were named after they was identified as proviral integration sites of the Moloney murine leukemia virus [1]
When macrophages are stimulated with lipopolysaccharides (LPS), large molecules that are a major component of the outer membrane of gram-negative bacteria, by binding to a potent immune receptor, Toll like receptor 4 (TLR4), it induces activation of nuclear factor kappa-B (NF-κB) [8] and inflammatory responses, including production and release of pro-inflammatory cytokines [9]
Members of the PIM kinase family are known as oncogenes, and many studies have been conducted on the 2r.o7l.eKoMf UPI‐M470inDteucrmeaosreidgeLnPeSs‐iIsnd[1u2c]e.d RPreoc‐eInnftllaym, smtuatdoireysCoyntotkhineefsuinncRtiAonWo2f6t4h.7e CPeIlMls kinase family in the inflWame imnvaetostriygarteesdpothneseefhfaecvteobfeKenMaUtt‐r4a7c0tionngLaPttSe-nmtieodni.atPeIdMr-e1g,uolnateioonf tohfeinthflraeme matory cytokines PIM kinases, is sigKnMifiUca‐n47tl0y isnidgnuicfeicdanbtylycigdaercerteteassemdokLePiSn-inRdAuWce2d64u.7p-creelglsu[l7a]t,ioanndotfhepirnoh-iinbfitlaiomnmatory cytokine of PIM-1 in a dextrinacnlusoddiniugmILs-u1βlf,aTteNcFo-lαit,isamndicIeLm-6oidneRl iAmWpr2o6v4e.d7 ccoelllistis(Fbiygurreedu6Acin–Cg)t.hMe eoxrecoesvseirv,eKMU-470 reduced activity of macropLhPaSg-eisndanudcetdheuipm-rmeguunleatrieosnpoonfseILo‐1f βThp1roatnedinTh(F1i7gu[5r]e
Summary
PIM kinases are a family of serine/threonine kinases that were named after they was identified as proviral integration sites of the Moloney murine leukemia virus [1]. Recent studies demonstrated that PIM-1 plays an important role in inflammatory responses [5,6,7]. These results suggest that PIM-1 has promising potential as an anti-inflammatory target. Recruitment of the myeloid differentiation factor (MyD88) to the plasma membrane is crucial for the intracellular inflammatory signal cascade by TLR4 [10]. This cascade results in the downstream activation of NF-κB and mitogen-activated protein kinase (MAPK), which further activaiantcettrisvacatethiloleunlaeorxftinrNaflFca-emκlBlmulaaantordrysmigsiitngoanglae-lnre-cagacsutcilavadateteeddbypkTrinoLtaResi4ne [k1(0Ein]R.asKTeh),i(sMccA-aJsuPcKnad),eNwrHhesi(cu2hl)t-stfeuirnrmththeinreaadlcotkiwvianntsaetssreetahm(eJNK), and MexAtrPaKcelplu3l8arpasitghnwala-yresg[u1l1a]te. We alnsoaminevdeKsMtigUa-t4e7d0,tahnedpeoxtpelnotrieadl iotfs PanIMti-i-n1flaasmamnaatnortyi-ipnrflopamertmieastionrLyPtSa-rtgreeatteudsiRnAgWPI2M64-1.7scieRllNs.AW.e investigated the potential of PIM-1 as an anti-inflammatory target using PIM-1 siRNA
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