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PubMed1999

Uncoupling integrin adhesion and signaling: the betaPS cytoplasmic domain is sufficient to regulate gene expression in the Drosophila embryo.

Integrin cell surface receptors are ideally suited to coordinate cellular differentiation and tissue assembly during embryogenesis, as they can mediate both signaling and adhesion. We show that integrins regulate gene expression in the intact developing embryo by identifying two genes that require integrin function for their normal expression in Drosophila midgut endodermal cells. We determined the relative roles of integrin adhesion versus signaling in the regulation of these integrin target genes. We find that integrin-mediated adhesion is not required between the endodermal cells and the surrounding visceral mesoderm for integrin target gene expression. In addition, a chimeric protein that lacks integrin-adhesive function, but maintains the ability to signal, can substitute for the endogenous integrin and regulate integrin target genes. This chimera consists of an oligomeric extracellular domain fused to the integrin betaPS subunit cytoplasmic domain; a control monomeric extracellular domain fusion does not alter integrin target gene expression. Therefore, oligomerization of the 47-amino-acid betaPS intracellular domain is sufficient to initiate a signaling pathway that regulates gene expression in the developing embryo.

Amino Acid Sequence↗
PubMed2001

Specific tracheal migration is mediated by complementary expression of cell surface proteins.

Migration of the Drosophila tracheal cells relies on cues provided by nearby cells; however, little is known about how these signals specify a migratory path. Here we investigate the role of cell surface proteins in the definition of such a pathway. We have found that the PS1 integrin is required in the tracheal cells of the visceral branch, whereas the PS2 integrin is required in the visceral mesoderm; both integrins are necessary for the spreading of the visceral branch over its substratum. This is the first identification of a cell surface molecule with expression restricted to a subset of tracheal cells that all migrate in a given direction. We have also found that expression of PS1 in the visceral branch is regulated by the genes that direct tracheal cell migration, showing that integrin expression is part of the cell-fate program that they specify. These results support a model in which signal transduction determines the tracheal migratory pathways by regulating the expression of cell surface proteins, which in turn interact with surface molecules on the surrounding cell population.

Animals↗
PubMed2004

Methotrexate markedly reduces the expression of vascular E-selectin, cutaneous lymphocyte-associated antigen and the numbers of mononuclear leucocytes in psoriatic skin.

A positive correlation between disease severity and the frequency of cutaneous lymphocyte-associated antigen (CLA)-positive T cells in the blood of untreated patients with psoriasis has been previously observed. A dose-dependent inverse relationship between disease severity and the frequency of circulating CLA(+) T cells in psoriasis patients on methotrexate (MTX) treatment is reported. Circulating T cells from a patient with psoriasis were monitored for CLA expression on a daily basis for 5 weeks. A decrease in the intensity and frequency of CLA(+) mononuclear leucocytes was consistently observed in the blood during the first 3-4 days after each MTX intake, but the CLA expression increased thereafter until the next weekly dose was taken. The MTX treatment of this patient was then discontinued for 16 days, and a marked subjective exacerbation was reported within 9 days, which was confirmed objectively (laser Doppler perfusion imaging) after 11 and 16 days. Biopsies taken 4 days after the last MTX intake showed only a few mononuclear leucocytes in lesional skin, but the exacerbation coincided with a marked increase in CLA expression by mononuclear blood leucocytes, followed by an increase in endothelial E-selectin and a striking influx of CLA(+) mononuclear cells into lesional skin. Conversely, a clinical improvement after the patient resumed the MTX treatment was associated with reduction in CLA expression by mononuclear cells in the blood, downregulation of endothelial E-selectin and an approximate threefold decrease in mononuclear leucocyte infiltration of lesional skin. No MTX-associated changes were detected in the expression of very late antigen-4, vascular cell-adhesion molecule-1 nor the late activation marker CD25. It is concluded that MTX decreases the expression of CLA and E-selectin and that this may be a major mechanism for the therapeutic effect of MTX on psoriatic skin lesions.

Antigens, CD↗
PubMed2004

Bovine respiratory syncytial virus infection influences the impact of alpha- and beta-integrin-mediated adhesion of peripheral blood neutrophils.

Neutrophil migration into the airways and pulmonary tissue is a common finding in bovine respiratory syncytial virus (BRSV) infections. Although neutrophil trans-endothelial migration in general depends on beta2-integrins, alternative integrins such as the alpha4-integrins have been implicated. In this study, rolling and firm adhesion of peripheral blood neutrophils isolated from healthy and BRSV-infected calves to tumour necrosis factor (TNF)-alpha activated pulmonary endothelium was investigated under flow conditions in vitro. For neutrophils obtained from healthy animals, inhibition of the beta2-integrin reduced firm adhesion to 63% and inhibition of alpha4-integrin to 73% compared with untreated controls. Inhibition of both integrins reduced firm adhesion to 25%. Rolling velocity, which is used as a parameter for integrin involvement in neutrophil rolling, increased 1.7-fold by blocking beta2-integrin and was significantly augmented to 2.5-fold by blocking both alpha4- and beta2-integrins. For neutrophils obtained from BRSV-infected animals, however, rolling velocities at 10 days after infection (p.i.) were not influenced by blocking adhesion of alpha4- and beta2-integrins, indicating that these integrins did not support neutrophil rolling. In addition, the inhibition of firm adhesion by blocking both alpha4- and beta2-integrins was reduced significantly 9 days post-infection, resulting in a residual 68% neutrophil binding at 9 days p.i. Non-blocked firm adherence was not reduced, indicating that binding was achieved by other mechanisms than through alpha4- and beta2-integrins. These results demonstrate an important function for alpha4- and beta2-integrins in rolling and firm adherence of bovine neutrophils, to TNF-alpha-activated endothelium and show the dynamic use of these integrins for adhesion and migration by neutrophils in the course of BRSV infection.

Animals↗
PubMed2005

New insights into Drosophila larval haemocyte functions through genome-wide analysis.

Drosophila blood cells or haemocytes comprise three cell lineages, plasmatocytes, crystal cells and lamellocytes, involved in immune functions such as phagocytosis, melanisation and encapsulation. Transcriptional profiling of activities of distinct haemocyte populations and from naive or infected larvae, was performed to find genes contributing to haemocyte functions. Of the 13 000 genes represented on the microarray, over 2500 exhibited significantly enriched transcription in haemocytes. Among these were genes encoding integrins, peptidoglycan recognition proteins (PGRPs), scavenger receptors, lectins, cell adhesion molecules and serine proteases. One relevant outcome of this analysis was the gain of new insights into the lamellocyte encapsulation process. We showed that lamellocytes require betaPS integrin for encapsulation and that they transcribe one prophenoloxidase gene enabling them to produce the enzyme necessary for melanisation of the capsule. A second compelling observation was that following infection, the gene encoding the cytokine Spatzle was uniquely upregulated in haemocytes and not the fat body. This shows that Drosophila haemocytes produce a signal molecule ready to be activated through cleavage after pathogen recognition, informing distant tissues of infection.

Animals↗
PubMed2005

Platelet glycoprotein I(b)alpha and integrin alpha2 beta1 polymorphisms: gene frequencies and linkage disequilibrium in a population diversity panel.

Genetic variants in the GP1BA and ITGA2 genes have been proposed as potential modifiers for arterial vascular disease and bleeding disorders. Since ancestry may play an important role in the prevalence of these variants, we sought to determine their allele frequency and linkage disequilibrium in a collection of 1064 DNA samples from 51 ethnic groups. We studied haplotypes of ITGA2 defined by single nucleotide substitutions at positions -52, 807, and 1648, and GP1BA variants defined by sequence changes in positions -5 (Kozak), 1018 (T145M, HPA-2) and 1285 (VNTR A, B, C and D). Frequency of haplotypes of ITGA2 showed considerable variation across the different groups, with a higher prevalence of the haplotype -52C or T/807C/1648A observed in African compared with caucasian and Asian populations. The haplotypes 52C/807T/1648A and -52T/807T/1648A were not observed in caucasians or South Americans. While relative frequencies of the GP1BA Kozak alleles were comparable across groups, the methionine allele (HPA-2b) showed a higher frequency in Africa (0.26) than in the other groups. We also observed a high prevalence of the VNTR B allele in the African and Israeli populations. Haplotype analysis revealed incomplete linkage disequilibrium between the HPA-2 and VNTR alleles. Incorporation of GP1BA variants into the set of SNPs already genotyped by the HapMap project disrupted the pre-existing haplotype block. These data provide a valuable resource for optimal selection of variants best tailored for association studies of vascular disease or bleeding disorders when examining individuals of different ancestral origins.

Alleles↗
PubMed1996

The role of alpha E beta 7 integrin (CD103) and E-cadherin in epidermotropism in cutaneous T-cell lymphoma.

Adhesion molecules such as integrins and cadherins are thought to play a critical role in T-cell migration and localization within the epidermis (epidermotropism). The purpose of this study was to correlate T-cell expression of the integrin CD103 and E-cadherin in cutaneous T-cell lymphoma (CTCL). Serial sections of skin biopsies from 22 patients with CTCL and 13 with benign reactive dermatitis were stained with antibodies to CD4, CD103, and E-cadherin by the avidin-biotin peroxidase technique. CD103 was expressed on single epidermotropic CD4+ T-cells in 9/9 early stage (patch/plaque) CTCL and 6/10 reactive dermatitis biopsies. Less than 30% of dermal T-cells expressed CD103. All 4/4 late stage (tumor) CTCL were CD103-. Epidermal aggregates of CD4+ T-cells (Pautrier's microabscesses) were CD103-. E-cadherin was expressed on epidermal keratinocytes and follicular and sweat gland epithelia but not on T-cells. We conclude that CD103 expression on cutaneous T-cells parallels the degree of epidermotropism exhibited in both neoplastic and inflammatory disorders of the skin. E-cadherin is not expressed on T-cells infiltrating the skin. Further investigation is necessary to further elucidate the interaction between CD103 and E-cadherin in facilitating trafficking of T-cells into the epidermis.

Antigens, CD↗
PubMed2004

Role of integrin CD103 in promoting destruction of renal allografts by CD8 T cells.

Infiltration of CD8(+)TCRalphabeta(+) T-effector populations (CD8 effectors) into graft epithelial compartments has long been recognized as a key lesion in progression of clinical renal allograft rejection. While the afferent phase of allograft immunity is increasingly well-defined, the efferent pathways by which donor-reactive CD8-effector populations access and ultimately destroy the graft renal tubules (rejection per se) have received remarkably little attention. This is an important gap in our knowledge of transplantation immunology, because epithelial compartments comprise the functional elements of most commonly transplanted organs including not only kidney, but also liver, lung, pancreas, and intestine. Furthermore, there is increasing evidence that attack of graft epithelial elements by CD8-effector populations not only causes short-term graft dysfunction but is also a major contributor to development of chronic allograft nephropathy and late graft loss, which now represent the salient clinical problems. Recent studies of the T-cell integrin, alpha(E)beta(7) (CD103), have provided insight into the mechanisms that promote interaction of CD8 effectors with graft epithelial compartments. The purpose of this communication is to review the known properties of the CD103 molecule and its postulated role in the efferent phase of renal allograft rejection.

Antigens, CD↗
PubMed1999

Expression of integrin alpha9 subunit and tenascin in oral leukoplakia, lichen planus, and squamous cell carcinoma.

OBJECTIVES: Integrin alpha9 subunit is a member of beta1 integrin family and binds tenascin (TN). It is expressed by stratified squamous epithelium and may be associated with cell differentiation and growth. We studied if the expression of alpha9 integrin and TN is altered in leukoplakia, lichen planus, and squamous cell carcinoma (SCC). METHODS: Frozen sections of tissue samples obtained from normal human keratinized (16 subjects) and non-keratinized (three subjects) oral mucosa, oral leukopakias with dysplasia (19 subjects), reticular type lichen planus (nine subjects), or oral mucosal SCC (23 subjects) were stained immunohistochemically with antibodies against alpha9 integrin and TN. RESULTS: In contrast to its most prominent localization at the cell membranes of the basal epithelial cells in the normal mucosa, alpha9 integrin was localized in a more diffuse pattern with focal loss of expression at the epithelial cell membranes in leukoplakic dysplasia, lichen planus, and SCC. In some areas of SCC, alpha9 integrin localized throughout all cell layers of the tumor epithelium. In most areas, alpha9 integrin colocalized with TN but in heavily inflamed areas there was focal loss of TN and alpha9 integrin at the basement membrane zone. CONCLUSIONS: The findings show that alpha9 integrin expression is altered in leukoplakic dysplasia, lichen planus, and SCC.

Carcinoma, Squamous Cell↗
PubMed2004

Expression of integrin subunits alpha2, alpha3, alpha5, alphav, beta1, beta3 and beta4 in different histological types of ameloblastoma compared with dental germ, dental lamina and adult lining epithelium.

OBJECTIVE: To analyze integrin expression and distribution in different histological types of ameloblastoma, compared with dental germ, dental lamina and adult lining epithelium. MATERIALS AND METHODS: Three-micrometer sections from paraffin-embedded specimens were evaluated employing a streptavidin-biotin immunohistochemical method and anti-integrin alpha2, alpha3, alpha5, alphav, beta1, beta3 and beta4 antibodies. RESULTS: All integrins were present in all specimens, exhibiting different patterns. In follicular ameloblastoma, the integrin staining was stronger in the periphery while integrin alpha2 was not present in the central cells. Acanthomatous ameloblastoma showed a similar pattern, with positive staining for integrins alpha3, alpha5, alphav, beta1 and beta4 in the metaplastic cells. In the unicystic, integrin staining was uniform except for integrins alpha5 and beta3 which showed weaker staining in the upper layers. In the plexiform ameloblastoma, dental germ and lamina integrin staining was uniform. In the adult lining epithelium, staining for integrins alpha2, alpha5 and beta4 was confined to the basal layer, while integrins alphav and beta3 were present in the basal and parabasal, with integrins alpha3 and beta1 in the upper layers. CONCLUSION: Acanthomatous, follicular and unicystic ameloblastomas showed integrin staining patterns similar to the adult lining epithelium while the plexiform ameloblastoma was similar to the dental germ and lamina.

Adult↗
PubMed1998

The PS integrins are required for a regulatory event during Drosophila wing morphogenesis.

The PS1 and PS2 integrins are required for morphogenesis of the adult Drosophila wing. Clonal analysis experiments have shown that both integrins are necessary to maintain adhesion between the dorsal and ventral wing epithelia. We have found that early in wing morphogenesis, the integrins are also required for a regulatory event, and this may explain why PS1 and PS2 must be expressed on opposite surfaces of the wing at the onset of pupariation. Overexpression of integrin subunits during this early phase can lead to separation of dorsal and ventral surfaces, and we present evidence here that this dominant phenotype (the Blistermaker phenotype) results from a gain of integrin function, as opposed to negative interference from free integrin subunits. A possible model for an integrin signaling requirement in the wing is discussed.

Animals↗
PubMed2003

Forces for morphogenesis investigated with laser microsurgery and quantitative modeling.

We investigated the forces that connect the genetic program of development to morphogenesis in Drosophila. We focused on dorsal closure, a powerful model system for development and wound healing. We found that the bulk of progress toward closure is driven by contractility in supracellular "purse strings" and in the amnioserosa, whereas adhesion-mediated zipping coordinates the forces produced by the purse strings and is essential only for the end stages. We applied quantitative modeling to show that these forces, generated in distinct cells, are coordinated in space and synchronized in time. Modeling of wild-type and mutant phenotypes is predictive; although closure in myospheroid mutants ultimately fails when the cell sheets rip themselves apart, our analysis indicates that beta(PS) integrin has an earlier, important role in zipping.

Animals↗
PubMed2003

Essential roles for ecdysone signaling during Drosophila mid-embryonic development.

Although functions for the steroid hormone ecdysone during Drosophila metamorphosis have been well established, roles for the embryonic ecdysone pulse remain poorly understood. We show that the EcR-USP ecdysone receptor is first activated in the extraembryonic amnioserosa, implicating this tissue as a source of active ecdysteroids in the early embryo. Ecdysone signaling is required for germ band retraction and head involution, morphogenetic movements that shape the first instar larva. This mechanism for coordinating morphogenesis during Drosophila embryonic development parallels the role of ecdysone during metamorphosis. It also provides an intriguing parallel with the role of mammalian extraembryonic tissues as a critical source of steroid hormones during embryonic development.

Animals↗
PubMed2005

Detection of integrins in human cataract lens epithelial cells and two mammalian lens epithelial cell lines.

AIM: To compare the incidence of various integrin subunits in human cataract anterior lens epithelial cells (A-LEC) and in two mammalian LEC lines. METHODS: Circular sections of anterior capsules with attached LEC were obtained during cataract surgery. Integrin subunits were immunolocalised in these anterior LEC and in a human and rabbit LEC line, using four monoclonal antibodies specific for subunits alpha2, alpha3, and alpha5, and beta subunit 2. RESULTS: All of these subunits were found in at least a proportion A-LEC samples as follows: alpha2 71%, alpha3 92%, alpha5 62%, and beta2 24%. The human LEC line was immunoreactive for alpha2 and alpha3 only. The rabbit lens epithelial cell line was immunoreactive for alpha5 but there was no staining for alpha2, alpha3, or beta2. CONCLUSION: The A-LEC and mammalian LEC lines showed a similarity in their pattern of integrin expression. As these integrins are receptors for extracellular matrix (ECM) components, they are likely to be associated with the attachment and migration of LECs that precedes capsular opacification. Therefore these cell lines may be useful in the elucidation of mechanisms involved the pathogenesis of capsule opacification.

Animals↗
PubMed2005

Modulation of alpha7-integrin-mediated adhesion and expression by platelet-derived growth factor in vascular smooth muscle cells.

We showed previously that the expression of alpha(7)-integrin in aortic vascular smooth muscle cells (VSMC) is enhanced in a rat model of atherosclerosis. In the present study, we investigated the effects of platelet-derived growth factor (PDGF) on alpha(7)-integrin expression and VSMC adhesion and migration. Expression of the alpha(7)-integrin gene was determined by real-time RT-PCR, whereas protein levels were determined by fluorescence-activated cell sorting analysis. PDGF increased alpha(7) cell surface protein expression (12 and 24 h: 3.3 +/- 0.8- and 3.6 +/- 0.4-fold, P < 0.05 vs. control) and mRNA levels (24 h: 3.1-fold, P < 0.05 vs. control) in a time-dependent manner. Actinomycin D and cycloheximide attenuated PDGF-induced increases in alpha(7)-integrin, indicating the involvement of de novo mRNA and protein synthesis. Treatment with the MAPK inhibitors PD-98059, SP-600125, and SB-203580 attenuated PDGF-induced increases in mRNA. In contrast, PD-98059 and SP-600125, but not SB-203580, attenuated PDGF-induced increases in cell surface protein levels. PDGF-treated VSMC adhered to laminin more efficiently (42 +/- 6% increase, P < 0.01), and this increase was partially inhibited by anti-alpha(7)-integrin function-blocking antibody. However, PDGF did not alter migration on laminin, and there was no effect of the anti-alpha(7)-integrin function-blocking antibody on basal or PDGF-stimulated migration. Immunofluorescence imaging revealed an increase in alpha(7)-integrin distribution along the stress fibers. Together, these observations indicate that PDGF enhances alpha(7)-integrin expression in VSMC and promotes alpha(7)-integrin-mediated adhesion to laminin.

Animals↗
PubMed2004

Regulation of alpha7-integrin expression in vascular smooth muscle by injury-induced atherosclerosis.

Injury of vascular smooth muscle cells (VSMCs) by allylamine (AAM) leads to phenotypic changes associated with atherogenic progression including increased proliferation, migration, and alterations in cell adhesion. In the present study, the relationship between AAM-induced vascular injury and expression of the alpha(7)-integrin subunit was investigated. The alpha(7)-mRNA and protein expression were examined using real-time RT-PCR, fluorescence-activated cell sorting analysis (FACS), immunohistochemistry, and immunoblotting. In cultured VSMCs from aortas of AAM-treated rats (70 mg/kg for 20 days), alpha(7)-mRNA levels were increased more than twofold compared with control cells. No change was seen in beta(1)-integrin expression. FACS analysis revealed increased cell surface expression of alpha(7)-protein (25 +/- 9%; *P < 0.05). AAM treatment of naive VSMCs enhanced alpha(7)-mRNA expression (2.4 +/- 0.7-fold, mean +/- SE; *P < 0.05). The increased alpha(7)-mRNA expression was attenuated by the amine oxidase inhibitor semicarbazide and the antioxidant pyrrolidine dithiocarbamate, which confirms a role for oxidative stress in modulating alpha(7)-expression. In vivo alpha(7)-mRNA and protein expression were enhanced in the aortas of AAM-treated rats. In addition, increased alpha(7)-integrin expression facilitated AAM VSMC adhesion to laminin more efficiently compared with control (51 +/- 2%; *P < 0.05). Chemical injury induced by AAM significantly enhances alpha(7)-integrin expression in VSMCs. These findings implicate for the first time the expression of alpha(7)-integrin during the response of VSMCs to vascular injury.

Allylamine↗
PubMed1999

The integrin alpha10 subunit: expression pattern, partial gene structure, and chromosomal localization.

Herein we report the cloning of cDNAs and incompletely processed hnRNAs from endothelia and heart that encode the alpha10 subunit forming part of the novel collagen type II-binding integrin alpha10beta1 of chondrocytes. Analysis of hnRNA clones and reported expressed sequence tags revealed the positions of 17 putative intron-exon splice junctions shared with those of the p150,95 (ITGAX) gene. Human alpha10 transcripts of 5.4 and 1.8 kb were not restricted to chondrocytes but, instead, were widely expressed in a panel of 24 tissue types, where the highest expression was found in muscle and heart. The human alpha10 subunit gene (ITGA10) was localized to band q21 of chromosome 1.

Amino Acid Sequence↗