ORP8与SPAG5相互作用并影响细胞周期

目的：筛选与氧化固醇结合蛋白相关蛋白8（Oyxterol binding protein related protein 8,ORP8）相互作用的蛋白质,为揭示ORP8在细胞中的功能及其机制提供线索,并根据相互作用蛋白质初步探索ORP8的功能。方法：构建重组诱饵质粒pGBKT7-ORP8m,利用GAL4酵母双杂交系统筛选人Universal cDNA文库,筛选出与ORP8相互作用的蛋白质,通过GSTPull-down以及免疫共沉淀（Co-immunoprecipitation,Co-IP）验证蛋白质相互作用,并通过流式细胞仪检测过表达ORP8对HepG2细胞周期的影响。结果：酵母双杂交筛选得到了精子相关抗原5（Homo sapiens sperm associated antigen 5,SPAG5）,体外GSTpull-down和Co-IP实验确证了ORP8-SPAG5的相互作用,流式细胞术显示ORP8过表达后与空载体相比,人肝癌细胞系HepG2的S期细胞数增加,G1期细胞数减少。结论：SPAG5是与ORP8相互作用的蛋白质,ORP8过表达影响人肝癌细胞系HepG2的细胞周期,可能通过SPAG5起作用。ORP8-SPAG5的相互作用为进一步研究ORP8在肝细胞中的功能及其机制提供了有用的线索     

酵母双杂交系统筛选GATA-1相互作用蛋白质及功能验证

目的 利用酵母双杂交技术从人脑cDNA文库中筛选与人GATA-1相互作用的蛋白质.方法 从人K562细胞中扩增出全长GATA1基因,设计引物将其3段截断体亚克隆入酵母表达载体pDBLeu中,转化至AH109感受态酵母中,利用酵母双杂交技术筛选人脑cDNA文库中与其相互作用的蛋白质,阳性克隆通过回转及免疫共沉淀试验进行验证,利用3xGATA荧光素酶报告基因对相互作用蛋白质进行功能验证.结果 成功构建出酵母诱饵蛋白表达质粒pDBLeu-GATA1（1）,pDBLeu-GATA1（2）,pDBLeu-GATA1（3）,筛到34个阳性克隆,用生物信息学分析及回转验证得到5个与GATA-1相互作用的候选蛋白,通过免疫共沉淀试验进一步验证,获得3个蛋白质能与GATA-1相互作用,分别是ECSIT,EFEMP1和GPS2.荧光素酶试验表明这3个蛋白质均能对GATA1的转录活性产生影响,证实它们之间的相互作用具有影响GATA1转录的功能.结论 应用酵母双杂交技术及免疫共沉淀试验,从人脑cDNA文库中成功获得3个与GATA-1相互作用并对其转录活性具有调节作用的蛋白质,为研究GATA1蛋白质的功能提供了新的线索.     

血管生成素与炎症性疾病

血管生成素（angiogenin,ANG）是首个被发现来源于肿瘤的具有血管生成能力的蛋白质,但其在炎症中的作用机制尚未完全阐明. 研究表明, ANG在炎症性疾病的发生发展中起重要作用,并与炎症的调控密切相关,而慢性炎症正是导致肿瘤形成、生长和转移的因素之一. 本文以ANG与炎症的关联为基础,结合我们的工作阐述ANG在炎症性疾病特别是肿瘤中的作用和调控机制,明确ANG与蛋白质的相互作用、对信号通路的调控及核内作用是其发挥功能的重要机制,也可能是调控肿瘤炎症的重要机制. 因而,深入研究ANG与炎症的关系不仅可加深我们对ANG兼具抗炎、抗新生血管双重功能的认识,更可为炎症性疾病的治疗提供潜在的作用靶点和新的思路和方法.     

血管生成素基因组结合序列的筛选与鉴定

血管生成素（angiogenin,ANG）调控细胞增殖、迁移、分化等生物学过程,但其作用的分子机制尚未完全明了. 目前认为,ANG可结合到rDNA区域促进rRNA转录,也可能与mRNA有结合.为全面鉴定细胞内可结合ANG的基因组序列,我们利用染色质免疫共沉淀结合DNA芯片技术（ChIP-chip）对HeLa细胞的基因组DNA进行了筛选,共获得了1 248个结合片段. 我们进一步分析了这些结合片段附近分布的基因,发现有699个可能受ANG结合调控的基因. 基因注释和聚类分析显示,这些可能受ANG调控的基因主要与肿瘤发生发展有关（特别是结直肠癌和前列腺癌）,并且与TGF-β和Wnt信号通路相关. 最后,我们验证了ANG不仅与WNT6、CCNE1、APC2、FZD8和EGFR基因的启动子区域有直接结合,而且调控其表达.以上研究结果为深入研究ANG的功能机制提供了线索.     

蛋白质相互作用数据库

随着“蛋白质组学”的蓬勃发展和人类对生物大分子功能机制的知识积累,涌现出海量的蛋白质相互作用数据。随之,研究者开发了300多个蛋白质相互作用数据库,用于存储、展示和数据的重利用。蛋白质相互作用数据库是系统生物学、分子生物学和临床药物研究的宝贵资源。本文将数据库分为3类：（1）综合蛋白质相互作用数据库;（2）特定物种的蛋白质相互作用数据库;（3）生物学通路数据库。重点介绍常用的蛋白质相互作用数据库,包括BioGRID、STRING、IntAct、MINT、DIP、IMEx、HPRD、Reactome和KEGG等。     

ORP8 与SPAG5 相互作用并影响细胞周期

目的:筛选与氧化固醇结合蛋白相关蛋白8(Oyxterol binding protein related protein 8,ORP8)相互作用的蛋白质,为揭示ORP8在细胞中的功能及其机制提供线索,并根据相互作用蛋白质初步探索ORP8的功能.方法:构建重组诱饵质粒Pgbkt7-ORP8m,利用GAL4酵母双杂交系统筛选人Universal Cdna文库,筛选出与ORP8相互作用的蛋白质,通过GST Pull-down以及免疫共沉淀(Co-immunoprecipitation,Co-IP)验证蛋白质相互作用,并通过流式细胞仪检测过表达ORP8对HepG2细胞周期的影响.结果:酵母双杂交筛选得到了精子相关抗原5(Homo sapiens sperm associated antigen 5,SPAG5),体外GST pull-down和Co-IP实验确证了ORP8-SPAG5的相互作用,流式细胞术显示ORP8过表达后与空载体相比,人肝癌细胞系HepG2的S期细胞数增加,G1期细胞数减少.结论:SPAG5是与ORP8相互作用的蛋白质,ORP8过表达影响人肝癌细胞系HepG2的细胞周期,可能通过SPAG5起作用.ORP8-SPAG5的相互作用为进一步研究ORP8在肝细胞中的功能及其机制提供了有用的线索     

GST pull-down联合质谱筛选（肌）营养不良短小蛋白结合蛋白1在小鼠睾丸组织中的相互作用蛋白质

（肌）营养不良短小蛋白结合蛋白1（dystrobrevin binding protein 1,dysbindin-1）是溶酶体相关细胞器生物发生复合体-1(biogenesis of lysosome related organelles complex 1, BLOC-1)的1个亚基,在多种组织细胞中广泛表达;然而,其在睾丸组织中的作用至今尚不明确。为寻找（肌）营养不良短小蛋白结合蛋白1在睾丸组织中的相互作用蛋白质,以进一步研究（肌）营养不良短小蛋白结合蛋白1在睾丸中的作用,本研究首先在Rosetta(DE3)菌种中表达可溶性GST-dysbindin-1融合蛋白,经谷胱甘肽 琼脂糖珠亲和纯化后,与小鼠的睾丸组织蛋白质孵育进行GST pull-down实验,并通过液相色谱串联质谱（LC MS/MS）分析筛选（肌）营养不良短小蛋白结合蛋白1在睾丸组织中的相互作用蛋白质。利用BioGPS数据库聚类在睾丸组织中高表达和特异性表达的互作蛋白质,运用DAVID6.8在线分析工具从细胞组分、分子功能、生物学过程和KEGG通路等方面对筛选出的互作蛋白质进行GO（gene ontology）富集分析。本实验共筛选出108个（肌）营养不良短小蛋白结合蛋白1在睾丸组织中的潜在互作蛋白质,其中98个为尚未报道的（肌）营养不良短小蛋白结合蛋白1相互作用蛋白质,7个为睾丸高表达蛋白质,5个为睾丸特异性表达的蛋白质。这些候选蛋白质主要分布在细胞质、细胞核、细胞膜、细胞外泌体等细胞组分中,通过与蛋白质、核酸等分子结合参与蛋白质翻译和转运、囊泡运输及凋亡等生物学过程以及氨基酸生物合成、溶酶体及蛋白酶体等生物学通路。我们推测,在睾丸组织中（肌）营养不良短小蛋白结合蛋白1可能通过与多种蛋白质相互作用参与精子的发生和受精等过程。     

乙酰转移酶基因NAA10的生物学功能及其在肿瘤中的作用

N端乙酰转移酶A（N-acetyltransferase A, NatA）复合体是真核生物最主要的N端氨基酸α位乙酰转移酶,N端α位乙酰转移酶10基因（N-α-acetyltransferase 10, NAA10）编码的N端α位乙酰转移酶10蛋白（N-α-acetyltransferase 10 protein, Naa10p）是NatA的催化亚基. Naa10p具备新生蛋白质N端氨基酸α位乙酰化活性、成熟蛋白质Lys残基ε位乙酰化活性以及对部分转录因子的协同调节作用. Naa10p能够通过调节细胞周期促进细胞增殖,通过调节雷帕霉素靶蛋白（mechanistic target of rapamycin, mTOR）通路促进细胞自噬,并通过多种不同的分子信号通路抑制细胞运动能力.根据乙酰化底物的不同,Naa10p还在细胞凋亡的调控中起双重作用. Naa10p参与的生物学过程还涉及血管生成和神经发育等. Naa10p在多种癌症组织中呈过表达,但其预后意义随肿瘤不同而有较大差别.对Naa10p的生理生化研究必将使我们对细胞的生理病理学过程及其机制的了解更加深入全面.本文将从蛋白质结构、机制功能及临床意义等不同角度系统地阐述NAA10的研究现状与进展.     

基于生物信息学的抑癌基因NDRG2相互作用蛋白预测及验证

NDRG2(N Myc downstream regulator gene 2)是NDRG 家族成员之一. 以往研究表明,该家族与细胞的增殖和分化有关. 而该分子参与的细胞信号通路及调节机制尚未阐明. 本研究利用保守蛋白间相互作用（interologs）的生物信息学方法预测NDRG2相互作用分子,并通过免疫共沉淀（Co-IP）及His pull-down蛋白体外结合实验方法对预测结果进行验证. 生物信息学软件预测和分析结果表明,细胞中存在多个可能与NDRG2发生相互作用分子.结合文献报道,从中选取了3个候选分子Gnb1、 Rgs16及 Rgs5进行分子生物学实验验证.Co-IP及His pull-down实验结果表明,3个候选分子中,Rgs5蛋白能够和NDRG2蛋白相互作用,而其它2个候选分子与NDRG2的相互作用未获得实验室方法的验证.研究结果表明,生物信息学分析与实验室验证相结合是一种高效省时的蛋白质相互作用研究策略.通过这种策略证实NDRG2可以与 Rgs5蛋白相互作用,为后续NDRG2功能的研究提供了有效的线索.     

胃癌及癌旁组织定量比较蛋白质组学研究

为寻找胃癌特异的肿瘤标记物,用于胃癌临床诊断及药物治疗靶点的选择,本研究采用荧光差异显示凝胶电泳（DIGE）技术分离并筛选 Cy3、Cy5 及 Cy2 荧光素标记的胃癌及对应癌旁组织差异表达蛋白质,用基质辅助激光解吸电离飞行时间质谱（MALDI-TOF MS）或串联质谱技术进行鉴定并分析。结果共筛选出 33 个差异表达蛋白质点,其中 9 个蛋白质点在胃癌组织中上调,24 个蛋白质点下调。对 22 个蛋白质点采用质谱技术成功鉴定,突变结蛋白、锰超氧化物歧化酶、热休克蛋白 60等在胃癌中高表达,热休克蛋白 27、前列腺素 F 合酶、硒结合蛋白 1、锌指蛋白 160、微管蛋白 α6、真核生物翻译延伸因子 1 α1 等在胃癌组织中低表达,并筛选出 5 个未知蛋白。这些差异表达蛋白可望成为胃癌诊断的特异标记物,并与胃癌的发生、发展及预后等有关,为胃癌的诊断、发生机制的研究提供了新的思路。     

Angiogenin enhances cell migration by regulating stress fiber assembly and focal adhesion dynamics

Angiogenin (ANG) acts on both vascular endothelial cells and cancer cells, but the underlying mechanism remains elusive. In this study, we carried out a co-immunoprecipitation assay in HeLa cells and identified 14 potential ANG-interacting proteins. Among these proteins, β-actin, α-actinin 4, and non-muscle myosin heavy chain 9 are stress fiber components and involved in cytoskeleton organization and movement, which prompted us to investigate the mechanism of action of ANG in cell migration. Upon confirmation of the interactions between ANG and the three proteins, further studies revealed that ANG co-localized with β-actin and α-actinin 4 at the leading edge of migrating cells. Down-regulation of ANG resulted in fewer but thicker stress fibers with less dynamics, which was associated with the enlargements of focal adhesions. The focal adhesion kinase activity and cell migration capacity were significantly decreased in ANG-deficient cells. Taken together, our data demonstrated that the existence of ANG in the cytoplasm optimizes stress fiber assembly and focal adhesion formation to accommodate cell migration. The finding that ANG promoted cancer cell migration might provide new clues for tumor metastasis research.     

Interaction between angiogenin and fibulin 1: evidence and implication

Angiogenin is an angiogenic factor involved in tumorigenesis. However, the mechanism of angiogenin's action remains elusive. In the present study, we identified fibulin 1, an extracellular matrix and plasma glycoprotein, as an angiogenin-interacting molecule by yeast two-hybrid screening. This interaction was further confirmed by two different approaches. First, fibulin 1 was co-immunoprecipitated with angiogenin by anti-angiogenin monoclonal antibody in vitro , suggesting angiogenin binds with fibulin 1 directly. Then fluorescence resonance energy transfer analysis showed that fibulin 1 interacted with angiogenin in COS-7 cells, showing that the binding could occur in a cellular context. As fibulin 1 plays an important role in cell proliferation, migration, adhesion, and stabilizes new-forming blood vessel wall, the interaction between fibulin 1 and angiogenin might underline one possible mechanism of angiogenin in angiogenesis and/or tumorigenesis.     

血管生成素研究的希望与挑战——浙江大学血管生成素研究

虽然血管生成素发现于1985年,但由于其性质上的特殊及研究条件的限制,人类对其功能的了解进展缓慢. 浙江大学血管生成素研究组建立于2001年,主要从蛋白质相互作用、基因转录调控、RNA代谢等层面研究血管生成素的功能机制,发现该蛋白能够与卵泡抑素、磷脂混杂酶1等蛋白质相互作用而细调rRNA的转录水平;在RNA转录中发挥表观遗传修饰调控因子作用;通过与细胞骨架相关蛋白的相互作用而促进细胞迁移;miR 409 3p通过直接靶向下调该蛋白的表达而发挥抑癌基因的作用. 同时,在模式生物斑马鱼中揭示了血管生成素同源基因对胚胎早期发育的影响. 本文全面回顾了我们14年来在血管生成素方面的研究进展,探讨了当前研究中存在的问题,并展望了未来的发展方向.     

Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen interacts with multifunctional angiogenin to utilize its antiapoptotic functions

Kaposi's sarcoma-associated herpesvirus (KSHV) is etiologically associated with the angioproliferative Kaposi's sarcoma (KS). KSHV infection and the expression of latency-associated nuclear antigen (LANA-1) upregulates the angiogenic multifunctional 123-amino-acid, 14-kDa protein angiogenin (ANG), which is detected in KS lesions and in KSHV-associated primary effusion lymphoma (PEL) cells. ANG knockdown or the inhibition of ANG's nuclear translocation resulted in decreased LANA-1 gene expression and reduced KSHV-infected endothelial and PEL cell survival (Sadagopan et al., J. Virol. 83:3342-3364, 2009). Further studies here demonstrate that LANA-1 and ANG colocalize and coimmunoprecipitate in de novo infected endothelial cells and in latently infected PEL (BCBL-1 and BC-3) cells. LANA-1 and ANG interaction occurred in the absence of the KSHV genome and other viral proteins. In gel filtration chromatography analyses of BC-3 cell lysates, ANG coeluted with LANA-1, p53, and Mdm2 in high-molecular-weight fractions, and LANA-1, p53, and Mdm2 also coimmunoprecipitated with ANG. LANA-1, ANG, and p53 colocalized in KSHV-infected cells, and colocalization between ANG and p53 was also observed in LANA-1-negative cells. The deletion constructs of ANG suggested that the C-terminal region of amino acids 104 to 123 is involved in LANA-1 and p53 interactions. Silencing ANG or inhibiting its nuclear translocation resulted in decreased nuclear LANA-1 and ANG levels, decreased interactions between ANG-LANA-1, ANG-p53, and LANA-1-p53, the induction of p53, p21, and Bax proteins, the increased cytoplasmic localization of p53, the downregulation of Bcl-2, the increased cleavage of caspase-3, and the apoptosis of cells. No such effects were observed in KSHV-negative BJAB cells. The phosphorylation of p53 at serine 15, which is essential for p53 stabilization and for p53's apoptotic and cell cycle regulation functions, was increased in BCBL-1 cells transduced with short hairpin RNA targeting ANG. Together, these studies suggest that the antiapoptosis observed in KSHV-infected cells and the suppression of p53 functions are mediated in part by ANG, and KSHV has probably evolved to utilize angiogenin's multiple functions for the maintenance of its latency and cell survival. Thus, targeting ANG to induce the apoptosis of cells latently infected with KSHV is an attractive therapeutic strategy against KSHV infection and associated malignancies.     

Fibulin binds to itself and to the carboxyl-terminal heparin-binding region of fibronectin.

Fibulin is a recently described extracellular matrix (ECM) and plasma glycoprotein (Argraves, W. S., Tran, H., Burgess, W. H., and Dickerson, K. (1990) J. Cell Biol. 111, 3155-3164). In this report, ligand affinity chromatography and solid-phase binding analyses were performed to determine which ECM protein(s) interact with fibulin. Fibulin-Sepharose bound two polypeptides of 240 and 100 kDa from the culture medium of metabolically radiolabeled fibroblasts. These two proteins were identified as fibronectin (FN) and fibulin, respectively, based on their electrophoretic behavior and reactivity with monoclonal antibodies. Consistent with the findings of affinity chromatography, fibulin bound to surfaces coated with FN (either plasma or cellular form) or fibulin but not with other ECM proteins, such as laminin, merosin, and types I and IV collagen. The binding of fibulin to solid-phase FN was estimated to have a Kd of 139 nM, whereas the Kd for self-interaction was 322 nM. Evaluation of proteolytic fragments from all regions of FN allowed a fibulin-binding site to be localized within a 23-kDa heparin-binding fragment containing type III repeats 13-14. Heparin did not compete for the interaction between fibulin and FN, suggesting that the binding sites for fibulin and heparin are distinct.     

Angiogenin interacts with ribonuclease inhibitor regulating PI3K/AKT/mTOR signaling pathway in bladder cancer cells

Angiogenin (ANG), a member of RNase A superfamily, is the only angiogenic factor that possesses ribonucleolytic activity. Recent studies showed that the expression of ANG was elevated in various types of cancers. Accumulating evidence indicates that ANG plays an essential role in cancer progression by stimulating both cancer cell proliferation and tumor angiogenesis. Human ribonuclease inhibitor (RI), a cytoplasmic protein, is constructed almost entirely of leucine rich repeats (LRRs), which are present in a large family of proteins that are distinguished by their display of vast surface areas to foster protein–protein interactions. RI might be involved in unknown biological effects except inhibiting RNase A activity. The experiment demonstrated that RI also could suppress activity of angiogenin (ANG) through closely combining with it in vitro. PI3K/AKT/mTOR signaling pathway exerts a key role in cell growth, survival, proliferation, apoptosis and angiogenesis. We recently reported that up-regulating RI inhibited the growth and induced apoptosis of murine melanoma cells through repression of angiogenin and PI3K/AKT signaling pathway. However, ANG receptors have not yet been identified to date, its related signal transduction pathways are not fully clear and underlying interacting mechanisms between RI and ANG remain largely unknown. Therefore, we hypothesize that RI might combine with intracellular ANG to block its nuclear translocation and regulate PI3K/AKT/mTOR signaling pathway to inhibit biological functions of ANG. Here, we reported for the first time that ANG could interact with RI endogenously and exogenously by using co-immunoprecipitation (Co-IP) and GST pull-down. Furthermore, we observed the colocalization of ANG and RI in cells with immunofluorescence staining under laser confocal microscope. Moreover, through fluorescence resonance energy transfer (FRET) assay, we further confirmed that these two proteins have a physical interaction in living cells. Subsequently, we demonstrated that up-regulating ANG including ANG His37Ala mutant obviously decreased RI expression and activated phosphorylation of key downstream target molecules of PI3K/AKT/mTOR signaling pathway. Finally, up-regulating ANG led to the promotion of tumor angiogenesis, tumorigenesis and metastasis in vivo. Taken together, our data provided a novel mechanism of ANG in regulating PI3K/AKT/mTOR signaling pathway via RI, which suggested a new therapeutic target for cancer therapy.     

The kallikrein-kinin and the renin-angiotensin systems have a multilayered interaction

Understanding the physiological role of the plasma kallikrein-kinin system (KKS) has been hampered by not knowing how the proteins of this proteolytic system, when assembled in the intravascular compartment, become activated under physiological conditions. Recent studies indicate that the enzyme prolylcarboxypeptidase, an ANG II inactivating enzyme, is a prekallikrein activator. The ability of prolylcarboxypeptidase to act in the KKS and the renin-angiotensin system (RAS) indicates a novel interaction between these two systems. This interaction, along with the roles of angiotensin converting enzyme, cross talk between bradykinin and angiotensin-(1-7) action, and the opposite effects of activation of the ANG II receptors 1 and 2 support a hypothesis that the plasma KKS counterbalances the RAS. This review examines the interaction and cross talk between these two protein systems. This analysis suggests that there is a multilayered interaction between these two systems that are important for a wide array of physiological functions.     

Fibulin 2, a Tyrosine O-Sulfated Protein,Is Up-regulated Following Retinal Detachment

Retinal detachment is the physical separation of the retina from the retinal pigment epithelium. It occurs during aging, trauma, or during a variety of retinal disorders such as age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, or as a complication following cataract surgery. This report investigates the role of fibulin 2, an extracellular component, in retinal detachment. A major mechanism for detachment resolution is enhancement of cellular adhesion between the retina and the retinal pigment epithelium and prevention of its cellular migration. This report shows that fibulin 2 is mainly present in the retinal pigment epithelium, Bruch membrane, choriocapillary, and to a lesser degree in the retina. In vitro studies revealed the presence of two isoforms for fibulin 2. The small isoform is located inside the cell, and the large isoform is present inside and outside the cells. Furthermore, fibulin 2 is post-translationally modified by tyrosine sulfation, and the sulfated isoform is present outside the cell, whereas the unsulfated pool is internally located. Interestingly, sulfated fibulin 2 significantly reduced the rate of cellular growth and migration. Finally, levels of fibulin 2 dramatically increased in the retinal pigment epithelium following retinal detachment, suggesting a direct role for fibulin 2 in the re-attachment of the retina to the retinal pigment epithelium. Understanding the role of fibulin 2 in enhancing retinal attachment is likely to help improve the current therapies or allow the development of new strategies for the treatment of this sight-threatening condition.     

Evolutionary analysis of human vascular endothelial growth factor, angiopoietin, and tyrosine endothelial kinase involved in angiogenesis and immunity

Human vascular endothelial growth factor (VEGF), angiopoietin (ANG) and tyrosine kinase with immunoglobulin and epidermal growth factor homology domains (TIE)-2 consist of a grouping of proteins that are involved in vascular homeostasis, vascular integrity and angiogenesis. There are nine proteins in the immediate VEGF family: VEGFA, VEGFB, VEGFC, VEGFD, VEGF-3, placental growth factor (PGF), VEGF receptor (VEGFR)-1, VEGFR-2, and VEGFR-1-related. They can be stimulated by cytokines to become involved in immune responses. By using in silico tools, we were able to identify several possible analogues or homologues of VEGF, ANG and TIE-2 in invertebrates. This is the first report to show that these proteins may be conserved through evolution. These proteins may have a role in vascular maintenance and immunity. In addition, since VEGF, ANG and TIE-2 have a role in mammalian immunity that is significantly influenced by cytokines, such as IL-1, this may indicate an interaction of the vascular system and the immune system over evolutionary time.