新型的Ⅱ类细胞因子受体--白介素22结合蛋白

白介素22结合蛋白为一种新型的Ⅱ类细胞因子受体家族成员,已弄清了其蛋白质结构,基因及其表达。它能直接结合IL－22,作为IL－22的拮抗剂,发挥着多种生物学功能。     

白介素26研究进展

白介素26属于Ⅱ类细胞因子的IL10亚家族的一个新成员,已弄清了其结构特征,基因表达及定位,功能受体复合物及信号转导,它在免疫学上的功能日益受到重视。     

巨核细胞生成调控相关细胞因子及其作用研究进展

造血干细胞分化生成巨核细胞是一个十分复杂的过程,包括造血干细胞动员及其向巨核系祖细胞分化,巨核系祖细胞增殖、分化生成未成熟巨核细胞,巨核细胞的成熟和血小板释放等过程。研究发现,造血干细胞动员及其向各系细胞分化的大部分过程都在一种称为"龛"的结构中进行,多种龛内信号分子参与了造血干细胞的动员和分化调控。该文对造血干细胞龛内参与造血干细胞动员和分化生成巨核细胞的几种重要细胞因子及其调控作用进行综述。     

SDF-1／CXCR4在造血干细胞动员相关研究新进展

造血干细胞移植（HSCT）已成为治疗血液系统疾病、实体瘤、代谢性和严重自身免疫性等疾病主要方法之一。GCSF介导的动员是一个复杂的、多步骤的过程,而基质细胞衍生因子（SDF-1）及其受体CXCR4在造血干细胞的的动员及归巢中发挥着重要的作用。近年来．以SDF01／CXCR4为动员靶点研制出的CXCR4拮抗剂——AMD3100,经临床实验证明它是一种安全有效的新的动员剂。     

胰岛素和瘦素抵抗的重要调控因子:细胞因子信号转导抑制因子-3

细胞因子信号转导抑制因子-3(Suppressor of Cytokine Signaling-3,SOCS-3)是细胞信号转导生理抑制剂家族重要成员之一,主要参与负调控生长激素、白介素(IL),肿瘤坏死因子(TNF)等细胞因子信号转导.最近发现,SOCS-3在胰岛素和瘦素抵抗中具有重要调控功能,且与糖尿病关系密切,是未来糖尿病基因治疗的新靶点.该文综述了近年来SOCS-3结构及其对胰岛素和瘦素抵抗的调控机制研究进展,并探讨SOCS-3在糖尿病中的作用.     

白介素-33对树突状细胞的免疫调控效应及其在疾病中的作用

白介素（interleukin,IL）-33是近年来广泛研究的白介素-1家族细胞因子。既往研究大多集中在IL-33对其经典靶细胞，如肥大细胞、2型固有淋巴细胞的作用。树突状细胞（dendritic cell,DC）是目前所知功能最强的专职抗原呈递细胞。已证实，IL-33可以通过其特异性受体对DC发挥免疫调控作用，进而影响机体免疫功能状态和介导疾病的发生与发展过程。本文就IL-33调控DC的作用及机制做一综述，为进一步探究其免疫效应与调理途径提供新线索。     

脐血造血细胞的体外扩增：2.造血细胞生长因子和培养液更换的作用

研究了造血干细胞生长因子、白介素-3、白介素-6、粒-巨噬细胞集落刺激因子、粒细胞集落刺激因子及红细胞生成素对脐血造血细胞体外培养的影响及其剂量关系,考察了造血细胞因子单独与联合作用对造血细胞体外培养的影响,证实细胞因子组合使用比细胞因子单独使用效果更好,发现SCF+IL-3+IL-6+GM-CSF+G-CSF+EPO组合对总细胞扩增最佳,SCF+IL-3+IL6+GM-CSF组合对CFU-GM扩增最佳。实验发现培养液更换可大大提高脐血造血细胞总数和祖细胞数产出。在每天更换50%培养液下,脐血总细胞数在第三周扩增了27倍,祖细胞数扩增了21倍。     

gp130介导的信号转导通路在哺乳动物着床中的作用

IL—6相关细胞因子家族成员包括LIF、IL-6、IL-11以及它们的共同受体gp130,在哺乳动物的着床过程中起着重要的作用。LIF敲除的小鼠不能着床。IL—11Rα敲除的小鼠不能完全发生蜕膜化,从而导致妊娠的失败。IL—6敲除的小鼠着床数和着床胚胎的存活率均降低。这些细胞因子通过与受体结合,激活下游信号分子STAT,从而形成了gp130/Jak／STAT信号转导通路,并且STAT3基因敲除的小鼠也不能着床。这些细胞因子通过gp130/Jak／STAT信号转导通路在着床过程中起着重要的作用。了解此信号通路在看床中的作用对解决一些不明原因的不孕症,以及开发着床相关的避孕药物等具有重要意义。     

诱导胚胎干细胞心肌定向分化的方法及其机制

胚胎干细胞是具有分化为各种类型组织细胞潜能的全能干细胞,可在体外大量扩增,细胞因子、激素、诱导剂和细胞内转录因子等可诱导和调控胚胎干细胞进行心肌细胞定向分化．这将使干细胞移植治疗心肌损伤性疾病成为可能。该文介绍胚胎干细胞定向心肌分化的诱导因素及其机制的研究进展。     

心肌再生途径的研究进展

心急梗塞等心脏疾病可造成心肌的损伤。相继会发生心室扩张、癍痕、心脏功能紊乱。目前时心脏疾病的治疗主要通过药物和器官移植,因药物治标不治本和移植器官匮乏限制了治疗的效果,严重影响病人的身体健康。最近研究发现,相关细胞因子或基因、干细胞移植可使损伤区心肌细胞和血管再生及诱导内源性干细胞转移,从而修复损伤心肌并恢复心脏功能。以上研究成果及其临床的应用将成为损伤性心肌有效的治疗途径。本文着重阐明了相关细胞因子、基因和干细胞移植时心肌再生作用机制的研究现状。     

Molecular cloning, expression, and characterization of a Ca2+-dependent nuclease of Arabidopsis thaliana

Yeast Pichia pastoris has been widely utilized to express heterologous recombinant proteins. P. pastoris expressed recombinant porcine interleukin 3 (IL3) has been used for porcine stem cell mobilization in allo-hematopoietic cell transplantation models and pig-to-primate xeno-hematopoietic cell transplantation models in our lab for many years. Since the yeast glycosylation mechanism is not exactly the same as those of other mammalian cells, P. pastoris expressed high-mannose glycoprotein porcine IL3 has been shown to result in a decreased serum half-life. Previously this was avoided by separation of the non-glycosylated porcine IL3 from the mixture of expressed glycosylated and non-glycosylated porcine IL3. However, this process was very inefficient and lead to a poor yield following purification. To overcome this problem, we engineered a non-N-glycosylated version of porcine IL3 by replacing the four potential N-glycosylation sites with four alanines. The codon-optimized non-N-glycosylated porcine IL3 gene was synthesized and expressed in P. pastoris. The expressed non-N-glycosylated porcine IL3 was captured using Ni-Sepharose 6 fast flow resin and further purified using strong anion exchange resin Poros 50 HQ. In vivo mobilization studies performed in our research facility demonstrated that the non-N-glycosylated porcine IL3 still keeps the original stem cell mobilization function.     

Cytokines and hematopoietic stem cell mobilization

Hematopoietic stem cell transplantation (HSCT) has become the standard of care for the treatment of many hematologic malignancies, chemotherapy sensitive relapsed acute leukemias or lymphomas, multiple myeloma; and for some non-malignant diseases such as aplastic anemia and immunodeficient states. The hematopoietic stem cell (HSC) resides in the bone marrow (BM). A number of chemokines and cytokines have been shown in vivo and in clinical trials to enhance trafficking of HSC into the peripheral blood. This process, termed stem cell mobilization, results in the collection of HSC via apheresis for both autologous and allogeneic transplantation. Enhanced understanding of HSC biology, processes involved in HSC microenvironmental interactions and the critical ligands, receptors and cellular proteases involved in HSC homing and mobilization, with an emphasis on G-CSF induced HSC mobilization, form the basis of this review. We will describe the key features and dynamic processes involved in HSC mobilization and focus on the key ligand-receptor pairs including CXCR4/SDF1, VLA4/VCAM1, CD62L/PSGL, CD44/HA, and Kit/KL. In addition we will describe food and drug administration (FDA) approved and agents currently in clinical development for enhancing HSC mobilization and transplantation outcomes.     

Analysis of cytokines in umbilical cord blood-derived multipotent stem cell

Human umbilical cord blood (UCB)-derived multipotent stem cells are regarded as valuable sources for cell transplantation and cell therapy. These cells, under appropriate culture conditions, can differentiate into a variety of cell lineages such as osteoblasts. chondrocyles, adipocytes, and neuronal cells. Based on their largeex vivo expansion capacity as well as their differentiation potential, UCB-derived multipotent stem cells may become a suitable source for clinical transplantation in tissue engineering and regenerative medicine. All modern protocols involve the use of cytokines with chemotherapy in order to increase the circulation of stem cells in the blood. Because UCB, in general, produce less cytokine, or have a lower frequency of cytokine producing cells compared to adult stem cells, further research in cytokines related to the cell proliferation, cellular adhesion and cell migration is necessary to improve the understanding of the basic mechanisms of stem cell mobilization. This paper gives an overview of the cytokines produced by UCB-derived multipotent stem cells, and strongly suggests that cytokine induction and signal transduction is important for the differentiation of these cells.     

An ex vivo model of hematopoietic stem cell mobilization

BACKGROUND: Mobilization of hematopoietic stem cells to the circulation facilitates their collection, thereby providing a non-marrow source of these cells for transplantation. Hematopoietic cytokine administration induces mobilization for most, but not all, donors. Because the underlying biology of mobilization is not well understood, improving the process on a rational basis is difficult. The design of an in vitro mobilization model was pursued to facilitate investigations of the process. METHODS: MS5 murine stromal cell line cells were grown to confluence on microporous transwell membranes. Murine femoral marrow plugs were placed on top of the prepared transwell membranes. The transwells were then seated in wells containing media and hematopoietic growth factors. Cells that were released from the marrow plugs over time and migrated through the stromal layer into the wells were assayed for stem cell/progenitor cell characteristics. RESULTS: Few or no GM-CSF (progenitors) were found in wells containing media alone or media plus mobilizing cytokines after 24 h. After 120 h, the numbers of cells in the cytokine-containing wells increased, as did the numbers of CD34(+) cells. Cells in the wells at the time progenitor cells were most frequent were shown to include side population (SP) hematopoietic stem cells. After 120 h in the presence of cytokines, cells pooled from the wells were transplanted to lethally irradiated mice. Eighty per cent of the transplanted mice survived 30 days or more, demonstrating that radioprotective stem cells were present in the wells. DISCUSSION: An ex vivo model has been designed that may aid investigations of the various steps of stem cell mobilization.     

Synergistic stimulation of fibroblast prostaglandin production by recombinant interleukin 1 and tumor necrosis factor

Mononuclear cell production of cytokines that stimulate fibroblast prostaglandin (PG) elaboration is an important mechanism by which mononuclear cells regulate fibroblast function. However, the soluble factors mediating these PG-stimulatory effects are incompletely understood. We characterized the effects on PG production by confluent normal lung fibroblasts of recombinant interleukin 1 alpha (IL 1 alpha), interleukin 1 beta (IL 1 beta) and tumor necrosis factor (TNF), alone and in combination. All three cytokines stimulated fibroblast PG production with both IL 1 peptides being significantly more potent than TNF. In addition, TNF interacted in a synergistic fashion with both IL 1 peptides to augment fibroblast PGE elaboration further. The stimulatory effects of the cytokines were almost entirely caused by an increase in PGE2 production and were reversed when the cytokine(s) were removed. These changes in PG production could not be explained by alterations in cell number and were completely negated by specific anticytokine antibodies. Recombinant gamma interferon, although synergizing with TNF in regulating other cellular functions, did not interact with TNF to augment fibroblast PGE elaboration. In addition, the synergistic interaction of IL 1 and TNF did not extend to all biologic effects of IL 1 since TNF did not augment the ability of IL 1 to stimulate thymocyte proliferation.     

Effects of cytokines on human thymic epithelial cells in culture: IL1 induces thymic epithelial cell proliferation and change in morphology

The role of thymic epithelium in T cell development has given rise to a number of studies, but less information is available concerning the factors regulating thymic epithelial cells (TEC) themselves. Several cytokines, natural or recombinant, were investigated for their effects on human TEC proliferation. This study presents evidence for the first time that human recombinant interleukin 1 (IL1) and IL1-containing mixed cytokine preparations induced DNA synthesis of TEC as measured in a 48-hr stimulation assay. The effects of IL1 were dose dependent and sustained in time. The following recombinant cytokines, IL2, IL3, IL4, interferon-gamma (IFN-gamma), IFN-alpha, tumor necrosis factor-alpha (TNF alpha), and TNF beta, as well as thymosin fraction 5 and Escherichia coli lipopolysaccharide (LPS), were not found to modify TEC proliferation but IFN-gamma and TNF alpha enhanced the effects of IL1. We also report that IL1 induced a profound change in the morphology of TEC. Our observations suggest that TEC are targets for the action of cytokines and emphasize the important role played by IL1 within the thymus.     

Transplantation of mesenchymal stem cells overexpressing interleukin‐10 induces autophagy response and promotes neuroprotection in a rat model of TBI

Autophagy, including mitophagy, is critical for neuroprotection in traumatic brain injury (TBI). Transplantation of mesenchymal stem cells (MSCs) provides neuroprotection and induces autophagy by increasing anti‐inflammatory cytokines, such as interleukin‐10 (IL‐10). To evaluate these effects of IL10 that are released by MSCs, we genetically engineered MSCs to overexpress IL10 and compared their effects to unaltered MSCs following transplantation near the site of induced TBIs in rats. Adult, male Sprague‐Dawley rats were divided into four groups: Sham + vehicle, TBI + vehicle, TBI + MSCs‐IL‐10 and TBI + MSCs‐GFP. Thirty‐six hours post‐TBI, the first two groups received vehicle (Hanks balance salt solution), whereas last two groups were transplanted with MSCs‐IL‐10 or MSCs‐GFP. Three weeks after transplantation, biomarkers for neurodegenerative changes, autophagy, mitophagy, cell death and survival markers were measured. We observed a significant increase in the number of dead cells in the cortex and hippocampus in TBI rats, whereas transplantation of MSCs‐IL‐10 significantly reduced their numbers in comparison to MSCs alone. MSCs‐IL‐10 rats had increased autophagy, mitophagy and cell survival markers, along with decreased markers for cell death and neuroinflammation. These results suggest that transplantation of MSCs‐IL‐10 may be an effective strategy to protect against TBI‐induced neuronal damage.     

Stem cell mobilization and harvesting by leukapheresis alters systemic cytokine levels in patients with multiple myeloma

Background aimsStem cell mobilization and harvesting by peripheral blood leukapheresis in patients with myeloma can alter plasma levels of certain cytokines. In the present study, we investigated the effects of these interventions on a larger group of cytokines.MethodsPlasma cytokine levels were determined in 15 patients with myeloma who were undergoing peripheral blood stem cell harvesting, and we compared the patients with healthy donors who were undergoing platelet apheresis.ResultsSeveral cytokines showed altered levels in patients with myeloma when examined after chemotherapy plus granulocyte colony-stimulating factor–induced stem cell mobilization. The most striking effect was increased levels of several CCL (CCL2/3/4) and CXCL (CXCL5/8/10/11) chemokines as well as increased thrombopoietin, interleukin 1 receptor antagonist, interleukin-4, granulocyte colony-stimulating factor and hepatocyte growth factor. Stem cell harvesting by apheresis altered the plasma levels of several mediators (CD40 ligand, interleukin 1 receptor antagonist, CCL5 and CXCL5/8/10/11). Apheresis in patients with myeloma had divergent effects on these chemokine levels, although they were all still significantly higher than for healthy individuals. Thrombapheresis in healthy individuals had only minor effects on plasma cytokine levels. Stem cell graft supernatants showed high levels of several cytokines, especially CCL and CXCL chemokines. Analyses of chemokine profiles in pre-apheresis plasma and graft supernatants suggested that such profiling can be used to detect prognostically relevant differences between patients.ConclusionsOur results demonstrate that patients with myeloma have an altered cytokine network during stem cell mobilization, and the network is further altered during stem cell harvesting by leukapheresis. These treatment- or procedure-induced alterations involve several mediators known to affect myeloma cell proliferation, migration and survival.