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1.
Löbel M Bauer S Meisel C Eisenreich A Kudernatsch R Tank J Rauch U Kühl U Schultheiss HP Volk HD Poller W Scheibenbogen C 《Cellular and molecular life sciences : CMLS》2012,69(18):3101-3113
In this study, we performed a comprehensive analysis of the effect of CCN1 on the migration of human immune cells. The molecule CCN1, produced by fibroblasts and endothelial cells, is considered as an important matrix protein promoting tissue repair and immune cell adhesion by binding various integrins. We recently reported that CCN1 therapy is able to suppress acute inflammation in vivo. Here, we show that CCN1 binds to various immune cells including T cells, B cells, NK cells, and monocytes. The addition of CCN1 in vitro enhances both actin polymerization and transwell migration. Prolonged incubation with CCN1, however, results in the inhibition of migration of immune cells by a mechanism that involves downregulation of PI3Kγ, p38, and Akt activation. Furthermore, we observed that immune cells themselves produce constitutively CCN1 and secretion is induced by pro-inflammatory stimuli. In line with this finding, patients suffering from acute inflammation had enhanced serum levels of CCN1. These findings extend the classical concept of CCN1 as a locally produced cell matrix adhesion molecule and suggest that CCN1 plays an important role in regulating immune cell trafficking by attracting and locally immobilizing immune cells. 相似文献
2.
Cell-cell adhesion is a critical property of all multi-cellular organisms and its correct regulation is critical during development,
differentiation, tissue building and maintenance, and many immune responses. The multi-talin-like FERM domain containing protein,
FrmA, is required during starvation-induced multi-cellular development of Dictyostelium cells. Loss of FrmA leads to increased cell-cell adhesion and results in impaired multi-cellular development, slug migration
and fruiting bodies. Further, mixing experiments show that FrmA null cells are excluded from the apex of wild-type mounds,
to which cells that normally form the organising centre known as the tip sort. These data suggest a critical role for FrmA
in regulating cell-cell adhesion, multi-cellular development and, in particular, the formation of the organising centre known
as the tip.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
Received 28 August 2008; received after revision 10 October 2008; accepted 21 October 2008 相似文献
3.
Thrombospondins: from structure to therapeutics 总被引:2,自引:0,他引:2
The thrombospondins (TSPs) are a family of five proteins that are involved in the tissue remodeling that is associated with embryonic development, wound healing, synaptogenesis, and neoplasia. These proteins mediate the interaction of normal and neoplastic cells with the extracellular matrix and surrounding tissue. In the tumor microenvironment, TSP-1 has been shown to suppress tumor growth by inhibiting angiogenesis and by activating transforming growth factor beta. TSP-1 inhibits angiogenesis through direct effects on endothelial cell migration and survival, and through effects on vascular endothelial cell growth factor bioavailability. In addition, TSP-1 may affect tumor cell function through interaction with cell surface receptors and regulation of extracellular proteases. Whereas the role of TSP-1 in the tumor microenvironment is the best characterized, the other TSPs may have similar functions. (Part of a Multi-author Review). 相似文献
4.
Malaria results in up to 2.5 million deaths annually, with young children and pregnant women at greatest risk. The great
majority of severe disease is caused by Plasmodium falciparum. A characteristic feature of infection with P. falciparum is the accumulation or sequestration of parasite-infected red blood cells (RBCs) in various organs, such as the brain, lung
and placenta, and together with other factors is important in the pathogenesis of severe forms of malaria. Sequestration results
from adhesive interactions between parasite-derived proteins expressed on the surface of infected RBCs and a number of host
molecules on the surface of endothelial cells, placental cells and uninfected RBCs. Some receptors for parasite adhesion have
been implicated in particular malaria syndromes, such as intercellular adhesion molecule 1 in cerebral malaria and chondroitin
sulfate A and hyaluronic acid in placental infection. The principal parasite ligand and antigen on the RBC surface, P. falciparum erythrocyte membrane protein 1 encoded by a multigene family termed var, is clonally variant, enabling evasion of specific immune responses. An understanding of these host-parasite interactions
in the context of clinical disease and immunity may reveal potential targets to prevent or treat severe forms of malaria.
Received 25 June 2001; received after revision 22 August 2001; accepted 24 August 2001 相似文献
5.
The main components in plasminogen activation include plasminogen, tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA), urokinase plasminogen activator receptor (uPAR), and plasminogen activator inhibitors-1 and –2 (PAI-1, PAI-2). These components are subject to extensive regulation and interactions with for example, pericellular adhesion molecules. Although uPA and tPA are quite similar in structure and have common inhibitors and physiological substrates, their physiological roles are distinct. Traditionally, the role of tPA has been in fibrinolysis and that of uPA in cell migration, especially in cancer cells. Recently several targets for tPA/plasmin have been found in neuronal tissues. The functional role of the PAIs is no longer simply to inhibit overexpressed plasminogen activators, and PAI-2 has an unidentified role in the regulation of cell death.Received 2 June 2004; received after revision 30 June 2004; accepted 20 July 2004 相似文献
6.
Endomannosidase processes oligosaccharides of α1-antitrypsin and its naturally occurring genetic variants in the Golgi apparatus 总被引:3,自引:0,他引:3
Torossi T Fan JY Sauter-Etter K Roth J Ziak M 《Cellular and molecular life sciences : CMLS》2006,63(16):1923-1932
Endomannosidase provides an alternate glucose-trimming pathway in the Golgi apparatus. However, it is unknown if the action
of endomannosidase is dependent on the conformation of the substrate. We have investigated the processing by endomannosidase
of the α1-antitrypsin oligosaccharides and its disease-causing misfolded Z and Hong Kong variants. Oligosaccharides of wild-type
and misfolded α1-antitrypsin expressed in castanospermine-treated hepatocytes or glucosidase II-deficient Phar 2.7 cells were
selectively processed by endomannosidase and subsequently converted to complex type oligosaccharides as indicated by Endo
H resistance and PNGase F sensitivity. Overexpression of endomannosidase in castanospermine-treated hepatocytes resulted in
processing of all oligosaccharides of wild-type and variants of α1-antitrypsin. Thus, endomannosidase does not discriminate
the folding state of the substrate and provides a back-up mechanism for completion of N-glycosylation of endoplasmic reticulum-escaped glucosylated glycoproteins. For exported misfolded glycoproteins, this would
provide a pathway for the formation of mature oligosaccharides important for their proper trafficking and correct functioning.
Received 18 April 2006; received after revision 12 June 2006; accepted 15 June 2006 相似文献
7.
Atherosclerosis is a complex inflammatory disease involving cellular migration and interaction. Vascular injury in response
to different cardiovascular risk factors enhances endothelial dysfunction, which in turn promotes the expression of inflammatory
markers and transendothelial leukocyte migration. Recruitment of leukocytes from the blood stream into the vessel intima is
a crucial step for the development of the disease. Recent findings have highlighted the role of chemokines, chemokine receptors,
adhesion molecules, and gap junctions in this process by acting as chemoattractant, adhesive, or intercellular communication
molecules. In this short review, we summarize new data concerning the different steps from leukocyte arrest to transendothelial
migration and discuss potential new therapeutic approaches concerning these processes.
Received 15 March 2006; received after revision 19 May 2006; accepted 13 June 2006 相似文献
8.
Sarah De Clercq Olivier Zwaenepoel Evelien Martens Joël Vandekerckhove Aude Guillabert Jan Gettemans 《Cellular and molecular life sciences : CMLS》2013,70(5):909-922
The T cell integrin receptor LFA-1 orchestrates adhesion between T cells and antigen-presenting cells (APCs), resulting in formation of a contact zone known as the immune synapse (IS) which is supported by the cytoskeleton. L-plastin is a leukocyte-specific actin bundling protein that rapidly redistributes to the immune synapse following T cell–APC engagement. We used single domain antibodies (nanobodies, derived from camelid heavy-chain only antibodies) directed against functional and structural modules of L-plastin to investigate its contribution to formation of an immune synapse between Raji cells and human peripheral blood mononuclear cells or Jurkat T cells. Nanobodies that interact either with the EF hands or the actin binding domains of L-plastin both trapped L-plastin in an inactive conformation, causing perturbation of IS formation, MTOC docking towards the plasma membrane, T cell proliferation and IL-2 secretion. Both nanobodies delayed Ser5 phosphorylation of L-plastin which is required for enhanced bundling activity. Moreover, one nanobody delayed LFA-1 phosphorylation, reduced the association between LFA-1 and L-plastin and prevented LFA-1 enrichment at the IS. Our findings reveal subtle mechanistic details that are difficult to attain by conventional means and show that L-plastin contributes to immune synapse formation at distinct echelons. 相似文献
9.
The rapid migration of intestinal epithelial cells (IEC) is important for the healing of mucosal wounds. We have previously
shown that polyamine depletion inhibits migration of IEC-6 cells. Akt activation and its downstream target GSK-3β have been
implicated in the regulation of migration. Here we investigated the significance of elevated phosphatidylinositol 3-kinase
(PI3K)/Akt signaling on migration of polyamine-depleted cells. Polyamine-depleted cells had high Akt (Ser473) and GSK-3β (Ser9)
phosphorylation. Pretreatment with 20 μM LY294002 (PI3K inhibitor) for 30 min inhibited phosphorylation of Akt, increased
migration by activating Rac1 in polyamine-depleted IEC-6 cells, and restored the actin structure similar to that in cells
grown in control medium. Treatment of cells with a GSK-3β inhibitor (AR-A014418) altered the actin cytoskeleton and inhibited
migration, mimicking the effects of polyamine depletion. Thus, our results indicate that sustained activation of Akt in response
to polyamine depletion inhibits migration through GSK-3β and Rac1.
Received 25 August 2006; received after revision 3 October 2006; accepted 16 October 2006 相似文献
10.
Profiling of the secreted proteins during 3T3-L1 adipocyte differentiation leads to the identification of novel adipokines 总被引:3,自引:0,他引:3
Wang P Mariman E Keijer J Bouwman F Noben JP Robben J Renes J 《Cellular and molecular life sciences : CMLS》2004,61(18):2405-2417
Adipose tissue is an endocrine organ capable of secreting a number of adipokines with a role in the regulation of
adipose tissue and whole-body metabolism. We used two-dimensional gel electrophoresis combined with mass spectrometry to
profile the secreted proteins from (pre)adipocytes. The culture medium of 3T3-L1 cells during adipocyte differentiation
was screened, and 41 proteins that responded to blocking of secretion by 20°C treatment and/or brefeldin A treatment
were identified. Prohibitin, stress-70 protein, and adhesion-regulating molecule 1 are reported for the first time as
secreted proteins. In addition, procollagen C-proteinase enhancer protein, galectin-1, cyclophilin A and C, and SF20/IL-25
are newly identified as adipocyte secreted factors. Secretion profiles indicated a dynamic environment including an
actively remodeling extracellular matrix and several factors involved in growth regulation.Received 15 June 2004; received after revision 26 July 2004; accepted 2 August 2004 相似文献
11.
E. Cohen-Hillel R. Mintz T. Meshel B.-Z. Garty A. Ben-Baruch 《Cellular and molecular life sciences : CMLS》2009,66(5):884-899
The chemokine CXCL8 is a powerful inducer of directional cell motility, primarily during inflammation. In this study, we found
that CXCL8 stimulation led to paxillin phosphorylation in normal neutrophils, and that both CXCL8 receptors (CXCR1 and CXCR2)
mediated CXCL8-induced paxillin phosphorylation. In CXCR2-transfected cells, the process depended on Gαi and Gαs coupling to CXCR2. Dominant negative (DN) paxillin increased CXCL8-induced adhesion and migration, indicating that endogenous
paxillin keeps migration at submaximal levels. Furthermore, using activating antibodies to β1 integrins, analyses with focal
adhesion kinase (FAK) DN variant (FRNK) and co-immunoprecipitations of FAK and paxillin, we found that β1 integrin ligation
cooperates with CXCL8-induced stimulation, leading to FAK activation and thereafter to FAK-mediated paxillin phosphorylation.
Our findings indicate that paxillin keeps directional motility at a restrained magnitude, and suggest that perturbations in
its activation may lead to chemotactic imbalance and to pathological conditions associated with excessive or reduced leukocyte
migration.
R. Mintz, T. Meshel: These authors contributed equally to this work.
Received 31 July 2008; received after revision 14 December 2008; accepted 16 December 2008 相似文献
12.
Intestinal epithelial barrier and mucosal immunity 总被引:5,自引:0,他引:5
The mucosal immune system acts as a first line of defense against bacterial and viral infections while also playing a crucial role in the establishment and maintenance of mucosal homeostasis between the host and the outside environment. In addition to epithelial cells and antigen-presenting cells (dendritic cells and macrophages), B and T lymphocytes form a dynamic mucosal network for the induction and regulation of secretory IgA (S-IgA) and cytotoxic T lymphocyte (CTL) responses. This review seeks to shed light on the pathways of induction and regulation of these responses and to elucidate the role they simultaneously play in fending off pathogen invasion and maintaining mucosal homeostasis. 相似文献
13.
Bleifuss E Kammertoens T Hutloff A Quarcoo D Dorner M Straub P Uckert W Hildt E 《Cellular and molecular life sciences : CMLS》2006,63(5):627-635
Cell-penetrating peptides (CPPs) have been shown to improve antigen loading of dendritic cell vaccines. Here we asked whether
fusion of a CPP to a protein improves its immunogenicity when this fusion protein is directly applied as vaccine. We used
the cell-penetrating translocation motif (TLM) derived from the hepatitis B virus, because no size limitation of cargos has
been observed. Increased immunogenicity was observed when TLM was fused to ovalbumin (TLM-ova). TLM-ova was found to be superior
to ova in inducing proliferation and cytotoxicity of ova-specific CD8+ T cells in vitro and in vivo. Using ovalbumin-expressing thymoma cells (EG7-ova), an improved anti-tumor immune response was observed for TLM-ova vaccination
versus vaccination with ova. Moreover, TLM-ova vaccination induced a higher titer of anti-ovalbumin IgG2a antibodies compared
to ova. These data demonstrate that CPP-protein vaccines can improve cellular as well as humoral immune responses.
Received 16 November 2005; received after revision 12 December 2005; accepted 10 January 2006
†These authors contributed equally to this work 相似文献
14.
Human bystin was identified as a cytoplasmic protein directly binding to trophinin, a cell adhesion molecule potentially involved
in human embryo implantation. Although the trophinin gene is unique to mammals, the bystin gene (BYSL) is conserved across eukaryotes. Recent studies show that bystin plays a key role during the transition from silent trophectoderm
to an active trophoblast upon trophinin-mediated cell adhesion. Bystin gene knockout and knockdown experiments demonstrate
that bystin is essential for embryonic stem cell survival and trophectoderm development in the mouse. Furthermore, biochemical
analysis of bystin in human cancer cells and mouse embryos indicates a function in ribosomal biogenesis, specifically in processing
of 18S RNA in the 40S subunit. Strong evidence that BYSL is a target of c-MYC is consistent with a role for bystin in rapid protein synthesis, which is required for actively growing
cells.
Received 30 June 2007; received after revision 7 August 2007; accepted 29 August 2007 相似文献
15.
Tang J Wu YM Zhao P Yang XM Jiang JL Chen ZN 《Cellular and molecular life sciences : CMLS》2008,65(18):2933-2942
Mechanism of HAb18G/CD147 underlying the metastasis process of human hepatoma cells has not been determined. In the present
study, we found that integrin α3β1 colocalizes with HAb18G/CD147 in human 7721 hepatoma cells. The enhancing effect of HAb18G/CD147
on adhesion, invasion capacities and matrix metalloproteinases (MMPs) secretion was decreased by integrin α3β1 antibodies
(p<0.01). The expressions of integrin downstream molecules including focal adhesion kinase (FAK), phospho-FAK (p-FAK), paxillin,
and phospho-paxillin (p-paxillin) were increased in human hepatoma cells overexpressing HAb18G/CD147. Deletion of HAb18G/CD147
reduces the quantity of focal adhesions and rearranges cytoskeleton. Wortmannin and LY294002, specific phosphatidylinositol
kinase (PI3K) inhibitors, reversed the effect of HAb18G/CD147 on the regulation of intracellular Ca2+ mobilization, significantly reducing cell adhesion, invasion and MMPs secretion potential (p<0.01). Together, these results suggest that HAb18G/CD147 enhances the invasion and metastatic potentials of human hepatoma
cells via integrin α3β1-mediated FAK-paxillin and FAKPI3K-Ca2+ signal pathways.
Received 5 June 2008; received after revision 16 July 2008; accepted 23 July 2008 相似文献
16.
Until recently, the expression and primary function of the cell surface receptor CD40 and its ligand CD154 were considered
restricted to B and T lymphocytes, and their interactions required for the thymus-dependent humoral response. However, current
work from several groups challenges this view of the CD40/CD154 dyad as a mere mediator of lymphocyte communication. A variety
of non-lymphocytic cell types express both receptor and ligand, including hematopoetic and non-hematopoetic cells, such as
monocytes, basophils, eosinophils, dendritic cells, fibroblasts, smooth muscle, and endothelial cells. Accordingly, ligation
of CD40 mediates a broad variety of immune and inflammatory responses, such as the expression of adhesion molecules, cytokines,
matrix-degrading enzymes, prothrombotic activities, and apoptotic mediators. Consequently, CD40 signaling has been associated
with pathogenic processes of chronic inflammatory diseases, such as autoimmune diseases, neurodegenerative disorders, graft-versus-host
disease, cancer, and atherosclerosis. This review focuses on the synthesis and structure of CD40 and outlines CD154/CD40 signaling
pathways, and emphasizes the previously unexpected importance of the CD40/CD154 receptor/ligand dyad in a spectrum of immunoregulatory
processes and prevalent human diseases.
Received 10 January 2000; revised 16 June 2000; accepted 5 July 2000
RID="†"
ID="†" Review
RID="*"
ID="*" Corresponding author. 相似文献
17.
Yuliia Kaljas Chengqian Liu Maksym Skaldin Chengxiang Wu Qing Zhou Yuanan Lu Ivona Aksentijevich Andrey V. Zavialov 《Cellular and molecular life sciences : CMLS》2017,74(3):555-570
At sites of inflammation and tumor growth, the local concentration of extracellular adenosine rapidly increases and plays a role in controlling the immune responses of nearby cells. Adenosine deaminases ADA1 and ADA2 (ADAs) decrease the level of adenosine by converting it to inosine, which serves as a negative feedback mechanism. Mutations in the genes encoding ADAs lead to impaired immune function, which suggests a crucial role for ADAs in immune system regulation. It is not clear why humans and other mammals possess two enzymes with adenosine deaminase activity. Here, we found that ADA2 binds to neutrophils, monocytes, NK cells and B cells that do not express CD26, a receptor for ADA1. Moreover, the analysis of CD4+ T-cell subset revealed that ADA2 specifically binds to regulatory T cells expressing CD39 and lacking the receptor for ADA1. Also, it was found that ADA1 binds to CD16? monocytes, while CD16+ monocytes preferably bind ADA2. A study of the blood samples from ADA2-deficient patients showed a dramatic reduction in the number of lymphocyte subsets and an increased concentration of TNF-α in plasma. Our results suggest the existence of a new mechanism, where the activation and survival of immune cells is regulated through the activities of ADA2 or ADA1 anchored to the cell surface. 相似文献
18.
Forkhead transcription factors in immunology 总被引:5,自引:0,他引:5
19.
Cowan-Jacob SW 《Cellular and molecular life sciences : CMLS》2006,63(22):2608-2625
Our current understanding of the structure, mechanism of action and modes of regulation of the protein tyrosine kinase family
owes a great deal to structural biology. Structures are now available for more than 20 different tyrosine kinase domains,
many of these in multiple conformational states. They form the basis for the design of experiments to further investigate
the role of different structural elements in the normal function and regulation of the protein and in the pathogenesis of
many human diseases. Once thought to be too similar to be specifically inhibited by a small molecule, structural differences
between kinases allow the design of compounds which inhibit only an acceptable few. This review gives a general overview of
protein tyrosine kinase structural biology, including a discussion of the strengths and limitations of the investigative methods
involved.
Received 2 May 2006; received after revision 21 June 2006; accepted 9 August 2006 相似文献