| DCs as professional antigen-present cells bridge the innate immunity and acquired immunity.Under the normal conditions,DCs maintaining their immature stage reside in body tissues.But when virus invading or bacterial infection occurs,DCs are active for exerting their mature functions associating with low-regulating the ability of migration and antigen-up taken,but enforcing the antigen processing and presenting.Besides,the up-regulating the expression of co stimulatory and MHC-II molecules and elevated activated-cytokines secreting is also the feature of DCs maturation.So,it involves in very complex dynamic changes of signaling and transcription regulatory networks during DCs maturation.But the mechanism of accomplishing immune responses and holding the balance between multi-signals after functional sates transition of dendritic cells is still not clear.It has shown that T cell have over proliferation and malignant transformation in e2f1-dificient mice in early studies.This phenomenon partially associates with dysfunctional DCs caused by e2f1's deficiency.In accord with these reports,our previous works also prove that transcription factor E2F1 can suppress the maturation of dendritic cell and negatively regulate multi-pathways in cell.After analysis of the open database about transcription regulatory networks based on gene-expression chips,we find the PIK3ap1(also called as BCAP)is potential target of E2F1.Former research achievements show that BCAP existing in special immune cells,mainly involving in PI3K/AKT pathway regulation,has distinctive functions about cell activation and differentiation in B cells,NK and macrophage,respectively.Though some studies has shown there is enhanced ability of DCs in promoting T cells proliferation in bcap knockout mice,the further functional roles of BCAP is still blank in dendritic cells.We use primary dendritic cells induced from the human peripheral blood and bone marrow derived from bcap knockout mice and two cell lines(DC2.4 and RAW264.7)as research objects to uncover the mechanism about E2F1 regulating BCAP at transcriptional levels as well as the functional roles of BCAP in dendritic cells.Our results show that(1)E2F1 interacting with N-terminal of Spl interferes in Spl DNA binding with the promoter of BCAP,leading to the suppression of Spl mediated the transcription of bcap gene.Because of this regulation,BCAP and E2F1 show a tight reversed dynamic relationship during DCs maturation.(2)BCAP can form complex with p85? and Myd88,respectively,mediating two different pathways in DCs.Under the rest conditions,BCAP interacting with Myd88 interferes in Myd88-mediated NF-?B activation.This situation is reversed accompanying with BCAP dissociating with Myd88 and forming complex with p85? when Myd88-mediated TLRs pathways are activated by agonists.Because of this reversion,the PI3K/AKT,p38 MAPK and NF-?B pathways are triggered simultaneously in dendritic cells.(3)Comparing bcap knockout mice with wildtype mice,the phenotype and functions emerge more mature including elevated expression of cytokines(IL-6,TNF and IL-12 etc)and co-stimulatory molecules(CD80,CD86 and CD83),as well as the ability of promoting T proliferation and antigen-uptaken.Aslo,the low migration and severed death are observed in bcap knockout mice.(4)Meanwhile,by using the influenza virus invading in bcap knockout mice model,we find BCAP can negatively regulate DCs mediated immune response.In the present study,we have revealed a novel pathway consistent with E2F1>BCAP>PI3K/NF-?B in Dendritic cells.In which,BCAP played a dual functions simultaneously in regulating both PI3K and NF-?B activations through interaction with either MyD88 or p85? in resting and activated status respectively.Through this feedback pathway,BCAP served as negative regulator dynamicity in maintaining cell homeostasis during DCs maturation.The study elucidated a fundamental model of a feedback signaling network on how the cell to maintain its cellular homeostasis during immune responses... |
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