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PubMed1995

Interferon-beta downregulates expression of VLA-4 antigen and antagonizes interferon-gamma-induced expression of HLA-DQ on human peripheral blood monocytes.

We have studied the effect of recombinant human IFN-beta on the basal and IFN-gamma-induced expression of adhesion molecules and class II MHC antigens on human peripheral blood monocytes and on ICAM-1 (intercellular adhesion molecule-1) expression of a human umbilical vein endothelial cell line (EAhy 926). We show that IFN-beta downregulates both basal and IFN-gamma-induced expression of VLA-4 (very late activation antigen-4) antigen on monocytes, but has no effect on the expression of CD11a, CD11b, CD11c, L-selectin, CD18, ICAM-1, beta 1-integrin or CD44 on monocytes or ICAM-1 on EAhy 926 cells. We also show that IFN-beta antagonizes the IFN-gamma-induced expression of HLA-DQ-antigen, but not HLA-DR or HLA-DP antigens on monocyte surface. These findings may partially explain the beneficial effect of IFN-beta in multiple sclerosis, since VLA-4-antigen is critical for leukocyte recruitment into inflamed brain and downregulation of HLA-class II expression diminishes antigen presenting capacity of monocytes.

Cells, Cultured↗
PubMed2006

Regulation of integrin alpha10 expression in chondrocytes by the transcription factors AP-2epsilon and Ets-1.

Expression of integrin alpha10 is initiated at the beginning of chondrogenesis and continues throughout cartilage development in adult cartilage. In our study, we aim to identify regulatory sequences that control the cell-type specific expression of the human integrin alpha10 gene. Therefore, promoter constructs harboring 1139bp 5' of the transcriptional start site of the human integrin alpha10 gene were analyzed. Our experiments localized a promoter region that directs high levels of expression specifically in chondrocytes. A sequence analysis detected three consensus AP-2 binding sites within this functional domain. Functionality of these sites was tested and confirmed by cotransfection of AP-2 in a luciferase reporter assay. Interestingly, EMSA identified AP-2epsilon as the major AP-2 protein binding to the AP-2 consensus sequences. Additionally, Ets-1 was shown to be a positive regulator of the integrin alpha10 expression whereas Sox9 was irrelevant. Taken together, these results suggest that AP-2epsilon and Ets-1 are involved in the regulation of integrin alpha10 transcription in chondrocytes.

Cell Line↗
PubMed2004

Differential effects of interleukin 12 and interleukin 10 on superantigen-induced expression of cutaneous lymphocyte-associated antigen (CLA) and alphaEbeta7 integrin (CD103) by CD8+ T cells.

At both cutaneous and mucosal sites, interleukin (IL)-10, IL-12 and transforming growth factor (TGF)-beta are important regulators of chronic inflammatory disease, where cutaneous lymphocyte-associated antigen (CLA) and alphaE integrin (CD103) may be expressed. Stimulation with streptococcal pyrogenic exotoxin C (SpeC) increased the expression of CD103 by CD8+ but not CD4+ T cells. While adding IL-12 augmented the expression of CLA, superantigen-induced expression of CD103 was markedly suppressed by IL-12, which could be reversed by TGF-beta. Antibodies against TGF-beta inhibited, and a combination of anti-TGF-beta and IL-12 completely abrogated the induced CD103 expression. IL-10 strongly decreased the frequency of CLA+ and although not increasing the frequency of CD103+CD8+ T cells, the amount of CD103 expressed per cell was markedly increased. Thus, the expression of CLA and CD103 may be antagonistically regulated by IL-10 and IL-12 and the balance between these cytokines could influence the T cell migration of inflammatory cells into epithelial tissues.

Antigens, CD↗
PubMed2006

Integrin alpha 11 is a novel type I interferon stimulated gene.

Interferons (IFNs) are a family of cytokines that have many biological functions in the cell, including regulation of cellular growth, differentiation, immunomodulation, and viral replication by inducing a set of interferon stimulated genes (ISGs). Based on their structure and biological activities IFNs are subdivided into two groups: type I IFNs, which includes IFN-alpha and IFN-beta and type II IFNs, represented by IFN-gamma. The aim of this work was to investigate whether integrin alpha 11 (ITGA-11), a novel collagen-binding integrin, is responsive to type I IFN treatment. Our findings indicated that type I IFNs were able to induce the ITGA-11 mRNA levels in T98G cells. Increased levels of ITGA-11 protein were also observed in IFN-treated cells. The in vivo induction of ITGA-11 was detected in spleen and lungs of IFN-treated BALB/c mice. T98G cells infected with Murine encephalomyocarditis virus showed increased levels of ITGA-11 mRNA and protein. We observed that the ITGA-11 promoter has binding sites for transcriptional factors regulated by IFNs and the double-stranded RNA dependent protein kinase (PKR). Therefore we investigated the role of PKR in the induction of ITGA-11 by using a PKR deficient mouse embryo fibroblast cell line (MEFs). PKR(-/-) MEFs treated with IFN did not show increased levels of ITGA-11 protein nor mRNA although that could be promptly detected in wild type MEFs. Taken together our data suggest that ITGA-11 is a new interferon stimulated gene.

Animals↗
PubMed2006

Expression of CD103 identifies human regulatory T-cell subsets.

BACKGROUND: Analysis of naturally occurring T regulatory CD4+ (nTreg) cells in human diseases is hampered by the lack of specific surface marker. Indeed, the CD25 antigen, which is typically used to identify nTreg cells, is also expressed on activated effector T cells. OBJECTIVE: We sought to examine whether CD4+ T cells bearing CD103 are suppressor cells, regardless of CD25 coexpression. METHODS: We first compared freshly isolated tonsillar CD103+ CD25- cells with their CD103- CD25high counterparts for their capacity to suppress T-cell response and their expression of FoxP3 mRNA. Next CD103 was induced on neonatal or adult CD4+ T cells stimulated with allogeneic dendritic cells, and the CD103+ and CD103- fractions were compared as above. RESULTS: Tonsillar CD4+ CD103+ CD25- T cells displayed comparable suppressive activity and contained similar amounts of FoxP3 mRNA as their CD103- CD25high counterparts. In vitro-generated alloantigen-primed CD103+ cells coexpressed CD25, suppressed T-cell activation, and contained more FoxP3 mRNA than the CD103- CD25+ cells isolated from the same cultures. Finally, neonatal alloreactive cells contained more CD103+ Treg cells than their adult counterparts and, unlike the latter, became hyporesponsive to the priming alloantigens. CONCLUSIONS: The examination of CD103 and CD25 coexpression allows identification of 3 subsets of human CD4+ nTreg cells, and the detection of CD103 on CD4+ T cells identifies nTreg cells, regardless of CD25 coexpression. CLINICAL IMPLICATIONS: The greater induction of CD103+ suppressor cells by cord blood should be related to its successful clinical use as an alternative to adult bone marrow transplantation.

Age Factors↗
PubMed2006

Centrifugation enhances integrin-mediated transduction of dendritic cells by conventional and RGD-modified adenoviral vectors.

The level of antigen loading can impact on the capacity for dendritic cells (DC) to activate T cell responses. Several different approaches to adenoviral (Ad)-based transduction were therefore assessed for their effect on both transgene expression and T cell activation. While a conventional E1(-)/E3Delta Ad vector (Ad/GFP) produced a concentration-dependent expression of GFP, a modified vector expressing Arginine-Glycine-Aspartic Acid (RGD) sequence on its fiber knob (Ad-RGD/GFP) enhanced transgene expression by 9-20-fold at each MOI. The addition of centrifugal force (2000xg) during DC transduction with Ad/GFP also increased expression up to 20-fold. However, combining centrifugation with the Ad-RGD/GFP vector produced no effect on transduction rate and only a 1.5- to 2-fold increase in GFP expression, suggesting overlapping mechanisms of action. Consistent with this, exogenous RGD peptide blocked transduction regardless of the vector used, or the addition of centrifugal force, and transduction was primarily limited to DC expressing the CD51 integrin receptor. Ad vectors expressing ovalbumin (OVA) were used to assess transduced DC for their capacity to activate OVA-specific T cells. We observed a significant relationship between transgene expression and the capacity for T cell activation regardless of whether transgene expression was increased by using a higher MOI, an RGD-modified vector, or by employing centrifugal force. Furthermore, combining these approaches produced synergistic effects on T cell activation. We conclude that RGD-modified vectors and centrifugation both enhance DC transduction by increasing entry via integrin receptors and that the capacity for T cell activation can be optimized by combining approaches to achieve the highest possible level of transgene expression.

Adenoviridae↗
PubMed2004

A monoclonal antibody to CD11d reduces the inflammatory infiltrate into the injured spinal cord: a potential neuroprotective treatment.

The accumulation of inflammatory cells in the lesion of a spinal cord injury (SCI) enhances secondary damage, resulting in further neurological impairment. High-dose methylprednisolone (MP) treatment is the only accepted treatment for inflammation secondary to human SCI but is minimally effective. Using a rat SCI model, we devised an anti-inflammatory treatment to block the infiltration of neutrophils and hematogenous monocyte/macrophages over the first 2 days postinjury by targeting the CD11dCD18 integrin. Anti-CD11d mAb administration following SCI effectively reduced neutrophil and macrophage infiltrate into lesions by 70% and 36%, respectively, over the first 72 h post-SCI. MP also reduced neutrophil and macrophage infiltrate by 60% and 28%, respectively, but by different mechanisms. The immunosuppression caused by anti-CD11d treatment was not sustained, as inflammatory cell numbers were not different from those observed in untreated SCI control animals at 7 days postinjury. In contrast, in MP-treated animals, the number of macrophages was still suppressed in the lesion while neutrophil numbers were significantly increased. These results suggest that anti-CD11d mAb treatment following SCI will minimize the destructive actions associated with early, uncontrolled leukocyte infiltration into the lesion while permitting the positive wound healing effects of macrophages at later time points.

Animals↗
PubMed2004

Genomic organization and sequence variation of the human integrin subunit alpha8 gene (ITGA8).

The integrin alpha8 is highly expressed during kidney and lung development. alpha8-deficient mice display abnormal renal development suggesting that alpha8 plays a critical role in organogenesis. Therefore, it would be of considerable interest to understand the genomic structure, localization and sequence variation of the alpha8 gene. Using FISH and genomic database analysis, we show that alpha8 gene maps to chromosome 10p13 and consists of >200 kbp organized into 30 exons. Examination of 47 individuals from two different ethnic groups (European and African descent) identified 286 varying sites. The diversity of alpha8 is comparable to that of other regions within the human genome. Eight of the varying sites were located in the coding regions: six resulted in nonsynonymous substitutions of which two lead to non-conservative changes in protein. None of the sites showed significant deviation from Hardy-Weinberg equilibrium. We mapped the coding region single nucleotide polymorphisms (SNPs) onto a model of the predicted alpha8 structure and found all the SNPs were located in the "calf" of the extracellular domain. In the European population, the linkage disequilibrium statistic D' showed three blocks of relatively non-recombinant regions in the alpha8 gene while the African population showed more evidence of recombination. The observed patterns of the linkage disequilibrium statistic R2 suggest that a large number of sites will need to be genotyped to ensure coverage of the entire gene for genetic association studies. Identification of the sequence variation will allow genetic association studies of alpha8 in kidney and lung disease.

Base Sequence↗
PubMed2005

Alpha7 integrin mediates neurite outgrowth of distinct populations of adult sensory neurons.

The successful regeneration of peripheral branches of sensory neurons following injury is attributed to the presence of neurotrophins and interaction of regenerating axons with the extracellular matrix. Here, we show that the laminin receptor, alpha7beta1 integrin is a crucial mediator of neurite outgrowth from distinct populations of sensory neurons. Following sciatic nerve crush, alpha7 integrin is expressed by medium-large diameter, NF200-immunoreactive (IR), and medium diameter, CGRP-IR, neurons, but very few small diameter non-peptidergic neurons. The functional significance of alpha7 integrin expression following injury was addressed using dissociated adult rat and mouse sensory neurons. By using function-blocking antibodies and neurons isolated from alpha7 integrin null mice, we demonstrate that NGF- and NT-3-stimulated neurite outgrowth is reduced in the absence of alpha7 integrin signaling. In contrast, GDNF-stimulated neurite outgrowth is less dependent on alpha7 integrin. These results define an essential interaction between alpha7 integrin and laminin for mediating neurite outgrowth of subpopulations of injured adult sensory neurons.

Animals↗
PubMed2006

Survival and morphology of auditory neurons in dissociated cultures of newborn mouse spiral ganglion.

We have systematically characterized neuronal survival and growth in cultures derived from newborn/postnatal day 1 mouse cochlea. Dissociated cultures of the cochlear spiral ganglion provide an experimental environment in which to examine molecular mechanisms of survival, development and physiology of auditory neurons. To relate survival to the total number of neurons present in the source tissue, three cochleas from different newborn CD-1 mice were embedded in Araldite resin and serially sectioned at 5 mum thickness. All neurons were counted. To avoid overcounting, each section served as a lookup section for the next, giving 8240+/-423 (S.D.) neurons per ganglion. Cultures maintained in the presence of adjacent non-neural tissue, brain-derived neurotrophic factor, neurotrophin 3, leukemia inhibitory factor (LIF) and 10% fetal bovine serum returned the best overall survival (30%) at 42 h post-plating. Best overall survival required the continuous presence of a serum component(s) larger than 100,000 MW. Plating efficiency (number of neurons that attach to the well after 4 h) was similar in the presence or absence of LIF. Inclusion of LIF maintained 100% survival of plated neurons over 42 h of culture; without LIF, a large fraction of the neurons did not survive. LIF appeared to maintain survival by preferentially preserving a population of bipolar neurons, while having little effect on the number of monopolar neurons. This work provides quantitative measures of survival and morphology of auditory neurons in vitro. The results support the idea that survival of spiral ganglion neurons in vivo may depend on interactions with adjacent, non-neural tissue and raise the possibility that maintenance of bipolar morphology after hair cell damage may require biochemical mechanisms in addition to those induced by neurotrophins.

Animals↗
PubMed2006

Specialized extraembryonic cells connect embryonic and extraembryonic epidermis in response to Dpp during dorsal closure in Drosophila.

Dorsal closure in Drosophila embryogenesis involves expansion of the dorsal epidermis, followed by closure of the opposite epidermal edges. This process is driven by contractile force generated by an extraembryonic epithelium covering the yolk syncytium known as the amnioserosa. The secreted signaling molecule Dpp is expressed in the leading edge of the dorsal epidermis and is essential for dorsal closure. We found that the outermost row of amnioserosa cells (termed pAS) maintains a tight basolateral cell-cell adhesion interface with the leading edge of dorsal epidermis throughout the dorsal closure process. pAS was subject to altered cell motility in response to Dpp emanating from the dorsal epidermis, and this response was essential for dorsal closure. alphaPS3 and betaPS integrin subunits accumulated in the interface between pAS and dorsal epidermis, and were both required for dorsal closure. Looking at alphaPS3, type I Dpp receptor, and JNK mutants, we found that pAS cell motility was altered and pAS and dorsal epidermis adhesion failed under the mechanical stress of dorsal closure, suggesting that a Dpp-mediated mechanism connects the squamous pAS to the columnar dorsal epidermis to form a single coherent epithelial layer.

Animals↗
PubMed2006

Runx3 regulates dendritic epidermal T cell development.

The Runx3 transcription factor regulates development of T cells during thymopoiesis and TrkC sensory neurons during dorsal root ganglia neurogenesis. It also mediates transforming growth factor-beta signaling in dendritic cells and is essential for development of skin Langerhans cells. Here, we report that Runx3 is involved in the development of skin dendritic epidermal T cells (DETCs); an important component of tissue immunoregulation. In developing DETCs, Runx3 regulates expression of the alphaEbeta7 integrin CD103, known to affect migration and epithelial retention of DETCs. It also regulates expression of IL-2 receptor beta (IL-2Rbeta) that mediates cell proliferation in response to IL-2 or IL-15. In the absence of Runx3, the reduction in CD103 and IL-2Rbeta expression on Runx3(-/-) DETC precursors resulted in impaired cell proliferation and maturation, leading to complete lack of skin DETCs in Runx3(-/-) mice. The data demonstrate the requirement of Runx3 for DETCs development and underscore the importance of CD103 and IL-2Rbeta in this process. Of note, while Runx3(-/-) mice lack both DETCs and Langerhans cells, the two most important components of skin immune surveillance, the mice did not develop skin lesions under pathogen-free (SPF) conditions.

Animals↗
PubMed2006

alpha7 integrin expressing human fetal myogenic progenitors have stem cell-like properties and are capable of osteogenic differentiation.

During muscle development, precursor cells fuse to form myofibers. Following injury in adult muscle, quiescent satellite cells become activated to regenerate muscle in a fashion similar to fetal development. Recent studies indicate that murine skeletal myoblasts can differentiate along multiple cell lineages including the osteoblastic pathway. However, little is known about the multipotency of human myogenic cells. Here, we isolate myogenic precursor cells from human fetal and adult muscle by sorting for the laminin-binding alpha7 integrin and demonstrate their differentiation potential and alteration in adhesive behavior. The alpha7-positive human fetal progenitors were efficient at forming myotubes and a majority expressed known muscle markers including M-cadherin and c-Met, but were heterogeneous for desmin and MyoD expression. To test their pluripotent differentiation potential, enriched populations of alpha7-positive fetal cells were subjected to inductive protocols. Although the myoblasts appeared committed to a muscle lineage, they could be converted to differentiate along the osteoblastic pathway in the presence of BMP-2. Interestingly, osteogenic cells showed altered adhesion and migratory activity that reflected growth factor-induced changes in integrin expression. These results indicate that alpha7-expressing fetal myoblasts are capable of differentiation to osteoblast lineage with a coordinated switch in integrin profiles and may represent a mechanism that promotes homing and recruitment of myogenic stem cells for tissue repair and remodeling.

Antigens, CD↗
PubMed2004

Expression of a NOS transgene in dystrophin-deficient muscle reduces muscle membrane damage without increasing the expression of membrane-associated cytoskeletal proteins.

Muscular dystrophy that is caused by mutation of the membrane-associated, cytoskeletal protein called dystrophin, is accompanied by loss of a dystrophin-associated protein complex (DPC) that includes neuronal nitric oxide synthase (nNOS). Previous work showed that expression of a nNOS transgene in the dystrophin-deficient, mdx mouse greatly reduces muscle membrane damage. In this investigation, we test whether expression of a nNOS transgene in wild-type or mdx muscle increases expression of DPC proteins, or functionally related proteins in the integrin complex that are upregulated in dystrophin-deficiency, or affects expression of the dystrophin homolog, utrophin. Many members of the DPC are enriched in Western blots of cell membranes isolated from NOS transgenic muscle, compared to wild-type. Similarly, alpha7-integrin and the associated cytoskeletal proteins talin and vinculin are increased in NOS transgenic, non-dystrophic muscle. However, utrophin expression is unaffected by elevated NOS expression in healthy muscle. A similar trend in mRNA levels for these proteins was observed by expression profiling. Analysis of membrane preparations from mdx mice and NOS transgenic mdx mice shows that expression of the NOS transgene causes significant reductions in utrophin, talin, and vinculin. Expression profiling of mRNA from mdx and NOS transgenic mdx muscles also shows reduced expression of talin. Immunohistochemistry of mdx and NOS transgenic mdx muscle indicates that reduction in utrophin in NOS transgenic mdx muscle results from a decrease in regenerative fibers that express high levels of utrophin. Together, these findings indicate that the NOS transgene does not reduce dystrophinopathy by increasing the expression of compensatory, structural proteins.

Animals↗
PubMed2004

Effect of complement inhibition and heparin coating on artificial surface-induced leukocyte and platelet activation.

BACKGROUND: Exposure of blood to artificial surfaces, as in cardiopulmonary bypass, induces an inflammatory response involving complement, leukocyte and platelet activation. To elucidate the specific role of complement in this process, studies were performed on blood circulated in polyvinyl chloride tubing in the absence and presence of complement inhibitors. Parallel experiments were performed with heparin-coated polyvinyl chloride tubing, which is known to prevent complement and cell activation. METHODS: A novel experimental model was used, based on human whole blood anticoagulated with lepirudin. Complement activation products, myeloperoxidase, lactoferrin, and thrombospondin were quantified in enzyme immunoassays. Leukocyte CD11b expression and leukocyte-platelet conjugates were detected by flow cytometry. RESULTS: Increased levels of C3 activation products, alternative pathway convertase, and the terminal SC5b-9 complex, combined with unchanged levels of C1rs-C1-inhibitor complexes and marginal changes in C4 activation demonstrated that complement was activated through the alternative pathway. Granulocyte and monocyte CD11b expression and granulocyte-platelet conjugate formation were efficiently attenuated by blocking either factor D, C3, C5, or C5a receptor. In contrast, monocyte-platelet conjugate formation and release of myeloperoxidase, lactoferrin, and thrombospondin were not reduced by complement inhibition. Heparin-coated polyvinyl chloride tubing efficiently reduced all inflammatory markers studied, except for C1rs-C1-inhibitor complexes, which increased, consistent with the enhancing effect of heparin on C1-inhibitor function. This effect did not, however, reduce fluid-phase classic pathway activation induced by heat-aggregated immunoglobulin G. CONCLUSIONS: Leukocyte and platelet activation in response to artificial materials occur by mechanisms that vary in their dependence on complement. Heparin coating precludes both the complement-dependent and complement-independent reactions.

CD11 Antigens↗
PubMed2003

Interaction of plasminogen-related protein B with endothelial and smooth muscle cells in vitro.

Plasminogen-related protein B (PRP-B) closely resembles the N-terminal plasminogen activation peptide, which is released from plasminogen during conversion to plasmin. We have previously demonstrated that the steady-state level of mRNA encoding PRP-B is increased within tumor tissues, and that recombinant PRP-B antagonizes neoplastic growth when administered systemically to mice harboring tumors, but no insights into the cell targets of PRP-B have been presented. Employing serum-free medium optimized for culturing human endothelial or smooth muscle cells, we show that recombinant PRP-B inhibits basic fibroblast growth factor-dependent cell migration for both cell types, as well as tube formation of endothelial cells. Comparison with the angiogenesis inhibitors angiostatin and endostatin revealed similar results. Recombinant PRP-B is effective in promoting cell attachment of endothelial and smooth muscle cells, and antibody interference experiments reveal that the interaction of recombinant PRP-B with endothelial cells is mediated at least in part by alpha(v)-containing integrins. Inhibition of angiogenesis in vivo by PRP-B was demonstrated in the chicken chorioallantoic membrane assay. PRP-B and other antiangiogenic molecules may elicit metabolic perturbations in endothelial cells as well as perivascular mesenchymal cells such as smooth muscle cells and pericytes.

Animals↗
PubMed1994

Expression of adhesion molecules by endovascular trophoblast and decidual endothelial cells: implications for vascular invasion during implantation.

During the process of implantation, maternal spiral arteries within the decidua are invaded by trophoblast cells that adhere to and migrate along the luminal surface of the vascular endothelial cells. This phenomenon resembles the events that occur during the migration of neutrophils into an acute inflammatory site, therefore it is possible that similar mechanisms are involved. Indeed, previous observations have shown that endovascular trophoblast expresses the blood group-related antigen sialyl Le(x). In this study, we show, by immunohistology, the expression of both E- and P-selectin by vascular endothelial cells only in the decidua basalis and not in decidua parietalis. In contrast, ICAM-1 is expressed by all vascular endothelium throughout the decidua. Expression of VCAM-1 is variable at the implantation site, and is not expressed by vascular endothelial cells in decidua parietalis. Interestingly, we demonstrate the strong expression of a polysialylated form of NCAM by endovascular trophoblast. Our data suggests that vascular invasion by trophoblast is regulated by the expression of appropriate adhesion molecules which permit interaction between endovascular trophoblast and decidual endothelial cells.

Cell Adhesion Molecules↗