12a(综述,在人类SLE中IL-2转录受抑)

1568-9972/$-see front matter D 2005Elsevier B.V .All rights reserved.doi:10.1016/j.autrev.2005.08.009Transcriptional repression of interleukin-2in human systemiclupus erythematosusChristina G.Katsiari a,*,George C.Tsokos a ,baDept.of Cellular Injury,Walter Reed Army Institute of Research,Silver Spring,MD 20190,USAbDepartment of Medicine,Uniformed Services University,Bethesda,MD 20814,USAAvailable online 26September 2005AbstractT cells from patients with SLE produce decreased amounts of interleukin-2(IL-2),a central cytokine in the regulation of the immune response.We discuss herein the abnormalities underlying IL-2deficiency in SLE T cells.D 2005Elsevier B.V .All rights reserved.Keywords:Systemic lupus erythematosus;Interleukin-2;Transcriptional regulation1.IntroductionInterleukin-2(IL-2)is essential for both the promo-tion and the suppression of the immune response [1].T cells from patients and mice with SLE produce de-creased amounts of IL-2,which is believed to contrib-ute to increased susceptibility to infections,decreased activation-induced cell death (AICD)and the subse-quent extended survival of autoreactive lymphocytes [2].Furthermore,recent studies have revealed the vital role of IL-2in the development and function of regulatory cells [1],which are presumed important in the control of the systemic autoimmune response.2.Regulation of IL-2in normal T cellsThe production of IL-2is tightly controlled by sev-eral transcription factors that bind to the IL-2promoter[3].The function of these transcription factors depends on the activation state of the cell.Engagement of the TCR/CD3complex,especially in the presence of a co-stimulatory signal (e.g.via CD28),triggers a cascade of biochemical events (e.g.rise of intracellular calcium),which result in the activation of kinases,such as PKC and phosphatases,such as calcineurin,which in turn promote the binding of several transcription factors to the IL-2promoter leading to the production of IL-2.These transcription enhancers include NF-n B,NFAT,AP-1(c-fos/c-jun heterodimer)and the phosphorylated form of CREB (pCREB).Transcriptional regulation of IL-2in normal T cells is depicted in Fig.1.There is evidence that all binding sites on the IL-2promoter need to be occupied to ensure maximal transcription and production of IL-2[4].While termination and negative regulation of IL-2production are not well defined,it is generally perceived as a passive process dependent on the dissociation and inactivation of tran-scription factors.On the other hand,we have recently demonstrated that following T cell activation,the tran-scription factor CREM is also induced and replaces pCREB at the À180site resulting in the termination*Corresponding author.WRAIR,Bldg.503,Rm.1A32,Silver Spring,MD 20910,USA.Tel.:+13013199424;fax:+13013199133.E-mail address:chistina.katsiari@ (C.G.Katsiari).Autoimmunity Reviews 5(2006)118–121/locate/autrevof IL-2production[5].Therefore,it appears that the ratio of pCREB/CREM that occupies theÀ180site of the IL-2promoter determines the production of IL-2.3.Transcriptional repression of IL-2production in SLE T cellsAltered regulation of transcription determines IL-2 deficiency in SLE T cells.Initial studies from our group showed that SLE T cells display a decrease of the NF-n B p65subunit.Under physiologic conditions the p65/ p50heterodimer accounts for the NF n B-mediated IL-2 upregulation[6].SLE T cells express adequate amounts of p50,which,in the absence of p65,homodimerize conveying a repressor effect[7].The importance of p65 deficiency is furthermore supported by experiments showing that forced expression of p65in SLE T cells increased IL-2gene promoter activity[8].The cause underlying p65deficiency is currently unknown al-though it is postulated that increased caspase-8activity observed in SLE might bind and digest the p65chain. Subsequently,we showed that the transcription repres-sor CREM binding to theÀ180site of the IL-2pro-moter in SLE T cells is increased and directly inhibits IL-2production in these cells[9].Transfection of SLE T cells with a plasmid encoding antisense CREM lim-ited the expression of CREM and resulted in increased production of IL-2[5].In addition,CREM binding toFig.1.Transcriptional Regulation of IL-2in normal T cells.The decisive elements for the transcription of the IL-2lie within300bp upstream of the start codon of the IL-2gene promoter.Within these300bp several AP-1sites are found,which are closely related to adjacent NFAT sites,as well as an NF n B,a cAMP-responsive element(RE)(theÀ180site)and a CD28-RE site.Stimulation of T cells through CD3and CD28leads to downstream signaling of several pathways resulting in the activation of several transcription factors,which bind to the IL-2promoter and enhance the production of IL-2.In particular,activated calcineurin dephosphorylates NFAT,which in turn translocates to the nucleus where it binds to the NFAT sites of the IL-2promoter together with the Jun–Fos dimers.c-jun is phosphorylated by PKC or JNK and subsequently forms dimers with newly synthesized c-fos.c-jun/c-fos dimers(transcription factor AP-1)enter into the nucleus and targets AP-1binding sites.Following phosphorylation by PKC,CREB targets theÀ180site of the IL-2promoter.pCREB enhances the production of c-fos as well.PKC also phosphorylates IkB,which detaches from the p65and p50subunits of NF-n B,which in turn form heterodimers and enter into the nucleus to target the NF-n B sites.The role of the CD28-RE is not well understood.NF-n B,ATF-1and CREB are able to bind this site,which is believed to promote the stability of IL-2mRNA.Binding sites for the transcription factors Oct-1and Elf-1also exist in the proximal part of the IL-2promoter(not depicted)but their role is poorly characterized.C.G.Katsiari,G.C.Tsokos/Autoimmunity Reviews5(2006)118–121119the c-fos promoter in unstimulated live T cells from SLE patients is significantly increased.Increased bind-ing results in decreased transcription of c-fos gene, decreased production of c-fos protein and AP-1binding in the nuclei of SLE T cells[10].Therefore,CREM contributes to the decreased expression of IL-2by both binding directly to the IL-2promoter and limiting the AP-1binding through its action to the c-fos promoter. In order to identify pathways that lead to increased binding of CREM to the IL-2promoter in SLE T cells,we recently demonstrated that Ca2+/calmodulin-dependent kinase IV(CAMK-IV)is increased in the nuclei of SLE T cells and is involved in the overexpres-sion of CREM and its binding to the IL-2promoter [11].In addition,we have recently reported that the message,protein and enzymatic activity of the catalytic subunit of protein phosphatase2A(PP2Ac)are in-creased in SLE T cells[12].PP2A is the primary enzyme that leads to dephosphorylation of pCREB in T lymphocytes[13],and it has furthermore been shown to suppress the production of IL-2[14].It is therefore possible that in SLE T cells overexpression of PP2A leads to decreased levels of pCREB,resulting in im-paired transcriptional activation of the IL-2promoter.In addition,decreased levels of pCREB may permit CREM to occupy their commonÀ180binding site on the IL-2promoter and directly suppress IL-2pro-duction[5].Analogous mechanisms could also be in-volved in the decreased expression of c-fos and the decreased AP-1activity encountered in SLE T cells. The described abnormalities are summarized in Table1.4.ConclusionsIL-2deficiency in SLE T cells is determined at the transcriptional level.Currently,identified defects lead-ing to decreased IL-2production in SLE T cells include changes in the expression and function of the transcrip-tion factors NF n B,AP-1and CREM.Upstream signal-ing molecules such as CAMK-IV and possibly PP2A appear to have an active role in the events leading to the transcriptional repression of IL-2in SLE.The study of such molecules,apart from providing further insight into the mechanisms underlying IL-2deficiency in SLE,could ultimately address the paradox encountered in SLE T cells,where a robust calcium response upon activation is followed by decreased production of IL-2. References[1]Nelson BH.IL-2,regulatory T cells,and tolerance.J Immunol2004;172(7):3983–8.[2]Tsokos GC.Overview of cellular immune function in sys-temic lupus erythematosus.In:Lahita RG,editor.Systemic lupus erythematosus.New York7Academic Press;1999.p.17–54.[3]Tenbrock K,Tsokos GC.Transcriptional regulation of theinterleukin2in SLE T cells.Int Rev Immunol2004;23: 333–45.[4]Jain J,Loh C,Rao A.Transcriptional regulation of the IL-2gene.Curr Opin Immunol1995;7(3):333–42.[5]Tenbrock K,Juang YT,Tolnay M,Tsokos GC.The cyclicadenosine5V-monophosphate response element modulator sup-presses IL-2production in stimulated T cells by a chromatin-dependent mechanism.J Immunol2003;170:2971–6.Table1Mechanisms of IL-2deficiency in SLE T cellsIL-2promoterNF-n B binding siteA Expression of NF-n Bp65subunit Z—A p65/p50A Binding—z p50/50z HÀ180binding sitez Expression of CREM Z—z CREM z Binding(—A pCREB)A HAP-1binding siteA Expression of c-fos Z A c-fos/c-jun A Binding Other—z Nuclear expressionof CAMK-IVZ z CREM activity—z Expression of PP2Ac(Z A pCREB activity) Decreased binding of transcriptional enhancers(e.g.p65/p50form of NF-n B,c-fos/c-jun heterodimer and pCREB)and increased binding of transcriptional repressors(e.g.p50/p50form of NF-n B and CREM) lead to decreased activity of the IL-2promoter and decreased pro-duction of IL-2in SLE T cells.In a recent study CAMK-IV was shown to regulate the expression and function of CREM.Overexpres-sion of PP2Ac may furthermore explain the function ofÀ180binding site of the IL-2promoter in SLE T cells.Text in parenthesis() represent proposed mechanisms contributing to reduced IL-2produc-tion by SLE T cells.Take-home messages!SLE T cells produce decreased amounts of IL-2. !IL-2deficiency in SLE has been linked to increased susceptibility to infections,decreased activation-in-duced cell death and inappropriate survival of auto-reactive lymphocytes.!Decreased transcription is responsible for the IL-2 deficiency in SLE T cells.!Decreased expression of the transcriptional enhancers NF-n B and AP-1as well as increased expression of the transcriptional repressor CREM leads to decreased production of IL-2in SLE T cells.!Abnormalities in the function of upstream molecules such as CAMK-IV and PP2A appear to orchestrate the altered activity of transcription factors in SLE T cells.C.G.Katsiari,G.C.Tsokos/Autoimmunity Reviews5(2006)118–121 120[6]Lederer JA,Liou JS,Todd MD,Glimcher LH,Lichtman AH.Regulation of cytokine gene expression in T helper cell subsets.J Immunol1994;152:77–86.[7]Wong HK,Kammer GM,Dennis G,Tsokos G.C.Abnormal NF-kappaB activity in T lymphocytes from patients with systemic lupus erythematosus is associated with decreased p65-relA pro-tein expression.J Immunol1999;163(3):1682–9.[8]Herndon TM,Juang YT,Solomou EE,Rothwell SW,GourleyMF,Tsokos GC.Direct transfer of p65into T lymphocytes from systemic lupus erythematosus patients leads to increased levels of interleukin-2promoter activity.Clin Immunol2002;103(2): 145–53.[9]Solomou EE,Juang YT,Gourley MF,Kammer GM,Tsokos GC.Molecular basis of deficient IL-2production in T cells from patients with systemic lupus erythematosus.J Immunol 2001;166(6):4216–22.[10]Kyttaris VC,Juang YT,Tenbrock K,Weinstein A,Tsokos GC.Cyclic adenosine5V-monophosphate response element modula-tor is responsible for the decreased expression of c-fos andactivator protein-1binding in T cells from patients with systemic lupus erythematosus.J Immunol2004;173(5):3557–63. [11]Juang YT,Wang Y,Solomou EE,Li Y,Mawrin C,Tenbrock K,et al.Systemic lupus erythematosus serum IgG increases CREM binding to the IL-2promoter and suppresses IL-2production through CaMKIV.J Clin Invest2005;115(4):996–1005. [12]Katsiari CG,Juang Y-T,Kyttaris VC,Tsokos GC.Overexpres-sion of functional protein phosphatase2A catalytic subunit C (PP2Ac)in T cells from patients with systemic lupus erythema-tosus(SLE).Arthritis Rheum2005;50(9)[Abs No1598]. [13]Westphal RS,Anderson KA,Means AR,Wadzinski BE.Asignaling complex of Ca2+–calmodulin-dependent protein ki-nase IV and protein phosphatase2A.Science1998;280(5367): 1258–261.[14]Chuang E,Fisher TS,Morgan RW,Duerr JM,Vander HeidenMG,Gardner JP,et al.The CD28and CTLA-4receptors asso-ciate with the serine/threonine phosphatase PP2A.Immunity 2000;13(3):313–22.Antiphospholipid syndrome in patients with systemic lupus erythematosus treated by autologous hematopoietic stem cell transplantation.Systemic lupus erythematosus(SLE)is the most common disease associated with antiphospholipid syndrome (APS).Statkute L.et al.(Blood2005;106:2700–9)therefore,evaluated46patients with refractory SLE treated by autologous hematopoietic stem cell transplantation(HSCT)for a history of APS prior to transplantation.The prevalence of SLE-related APS in our patient population was61%(28of46patients with refractory SLE). Nineteen of28patients with APS had lupus anticoagulant(LA)or high titers of anticardiolipin antibodies (ACLAs),either immunoglobulin IgG or IgM,when evaluated at study entry.Six of8evaluable LA+patients became and remained LA-;5of7initially ACLA IgG+patients and9of11ACLA IgM+patients demonstrated normalization of ACLA titers when followed after HSCT.Eighteen of22patients refractory to chronic anti-coagulation discontinued anticoagulation therapy.There was no treatment-related mortality.Autologous HSCT may be performed safely in patients with APS and appears to be effective therapy for eliminating APLAs and preventing thrombotic complications in patients with SLE.Clinical and serological features of35patients with anti-Ki autoantibodies.The objective of this study was to analyze clinical and serological associations of anti-Ki antibodies.Cavazzana I. et al.(LUPUS2005;14:837–41)studied thirty-five patients with anti-Ki antibodies,using the CIE assay.All patients were affected by autoimmune disease:SLE and pSS were the most frequent diagnosis.The cohort was constituted by27female and eight males.Main clinical features were skin involvement(60%),xerophtalmia (48.6%),Raynaud’s phenomenon(43%),photosensitivity(34%),xerostomia(31.4%).CNS involvement was present in four and renal disease in seven cases.ANA,anti-dsDNA and RF were detected in100%,60%,and 34.5%.In SLE,anti-Ki was detected in6%of cases,more frequently in males compared to other SLE patients without anti-Ki(p b0.004).Nineteen anti-Ki positive patients affected by SLE showed more frequently malar rash and multiple autoantibody specificities compared to16anti-Ki positive patients with other diseases(p=0.044and p=0.003,respectively).The study confirms a preferential occurrence of anti-Ki antibodies in patients with sicca and skin involvement.Malar rash and multiple ANA specificities were significantly associated with SLE compared to other diseases in our study.C.G.Katsiari,G.C.Tsokos/Autoimmunity Reviews5(2006)118–121121。