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Results for “Integrin alpha6beta1”

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PubMed1995

Mitogenic activity of laminin on human melanoma and melanocytes: different signal requirements and role of beta 1 integrins.

The possible mitogenic activity of laminin (LN) on normal and neoplastic cells of the melanocyte lineage was tested by culturing growth-arrested human melanoma cells and neonatal foreskin melanocytes on LN. Serum-deprived, quiescent melanoma cells proliferated, in serum-free medium, in a dose-dependent fashion to immobilized LN as determined by [3H]thymidine incorporation, cell cycle analysis, and change in cell number. The mitogenic activity of LN on melanoma cells was not mediated through autocrine release of growth factors and was observed with primary or metastatic melanoma cells and with clones isolated from the same metastasis but only on cells expressing very late antigen (VLA)-3 and VLA-6 laminin receptors. Proliferation of melanoma cells to LN was significantly inhibited by a mAb to the beta 1 subunit of VLA integrins and by a combination of mAbs to the alpha subunits of VLA-3 and VLA-6. By contrast, LN did not act asa mitogen on human melanocytes expressing VLA-3 and VLA-6 and cultured in serum-free medium. However, a costimulatory activity of immobilized LN for proliferation of melanocytes was observed in the presence of a second signal provided by a set of different growth factors. The costimulatory activity of LN on melanocytes could be significantly inhibited by mAbs directed to the alpha and beta chain of VLA-6 but not to VLA-3. These data suggest that LN itself, and not growth factors possibly associated with it, can exert a mitogenic activity on quiescent human melanoma cells and that a change in the signal requirements for response to LN occurs upon neoplastic transformation in the melanocyte lineage. Furthermore, beta 1 integrins are differentially involved in the response of the normal and the neoplastic cells to LN, since VLA-3 and VLA-6 cooperate in the proliferation of neoplastic cells, while VLA-6 is relevant for the response of melanocytes.

Cell Division↗

PubMed1995

Regulation of polymorphonuclear neutrophil CD16 and CD11b/CD18 expression by matrix proteins during hypoxia is VLA-5, VLA-6 dependent.

We investigated the effects of hypoxia on matrix protein regulation of polymorphonuclear neutrophil (PMN) CD16 and CD11b/CD18 expression. Adherence of PMN to fibronectin increased CD16 expression during hypoxia over levels seen during normoxia, while adherence of PMN to either fibronectin or laminin increased CD11b/CD18 expression during hypoxia over levels seen during normoxia. Kinetics assays demonstrated a t1/2 approximately 60 min and 30 min of hypoxia for maximal up-regulation of CD16 and CD11b/CD18, respectively. Incubation of fluid-phase PMN with anti-VLA-5 (alpha 5/beta 1) and anti-VLA-6 (alpha 6/beta 1) mAbs blocked the effect of fibronectin and laminin on CD16 and CD11b/CD18 expression. Cross-linking of both fluid-phase and adherent PMN VLA-5 and VLA-6 receptors resulted in a progressive increase in CD16 and CD11b/CD18 expression during hypoxia, but not normoxia. Increases in CD16 and CD11b/CD18 expression resulted in increased E anti-Fc gamma RIII and EC3bi rosetting. Inhibition of GPLC activity and IP3 production with U73122 and cyclopiazonic acid blocked the ability of fibronectin to increase CD16 expression and E anti-Fc gamma RIII rosetting. Inhibition of protein tyrosine kinase with genistein and herbimycin A blocked the ability of laminin to increase CD11b/CD18 expression and EC3bi rosetting. Depletion of intracellular Ca2+ abrogated the effects of fibronectin and laminin on CD16 and CD11b/CD18 expression, while restoration of intracellular Ca2+ restored the ability of fibronectin and laminin to increase CD16 and CD11b/CD18 expression. These results demonstrate that during hypoxia integrin signaling via alpha 5/beta 1 and alpha 6/beta 1 results in the increased expression of CD16 and CD11b/CD18. This increase in receptor expression results in biologically active receptors and is dependent upon intracellular Ca2+, GPLC, and protein tyrosine kinase activity.

CD11 Antigens↗

PubMed1993

The alpha 6 beta 1 integrin is a laminin receptor for developing retinal neurons.

Cultured embryionic day 6 (E6) retinal neurons respond to laminin by making use of integrin receptors. We have recently shown that the laminin binding integrin receptor alpha 6 beta 1 is expressed in the chick retina on both retinal ganglion cells and other retinal neurons. Antibodies raised against a fusion protein containing a large fragment of the extracellular portion of the chick alpha 6 integrin subunit dramatically inhibit the interactions between E6 retinal neurons and laminin. These data show that alpha 6 beta 1 functions as a laminin receptor in these cells. In previous work we have also shown that the levels of the mRNA for alpha 6 decreases dramatically in retinal ganglion cells between E6 and E12. Data presented in this paper show that the decrease in alpha 6 mRNA is not prevented by ablation of the optic tectum, indicating that contact with the target is not a major cause for this decrease.

Animals↗

PubMed1995

Regulation of alpha 6 beta 1 integrin-mediated migration in macrophages.

Several integrin alpha subunits have structural variants that are identical in their extracellular and transmembrane domains but that differ in their cytoplasmic domains. In the present study, we examined the possibility that the A and B variants of the alpha 6 beta 1 integrin laminin receptor differ in function. P388D1 macrophages that had been transfected with the alpha A integrin subunit were 3-4 fold more migratory than P388D1 macrophages that had been transfected with the alpha 6 B integrin subunit. Deletion of the alpha 6 cytoplasmic domain markedly inhibited the ability of the alpha 6 beta 1 receptor to promote migration.

Calcium↗

PubMed1994

Adhesion to laminin is down-regulated upon retinoic acid-induced F9 cell differentiation: a role for alpha 6/beta 1 integrin.

F9 mouse teratocarcinoma cells have a high capacity to adhere to laminin and we identified alpha 6/beta 1 integrin as the principal laminin-binding protein present in these cells. F9 cells differentiated into parietal endoderm when monolayer cultures were treated with retinoic acid and dibutyryl cyclic AMP. In this process a decreased adherence to laminin was observed due to a lower expression of alpha 6/beta 1 integrin on the cell surface.

Animals↗

PubMed1995

Alpha 3 beta 1 and alpha 6 beta 1 integrins mediate laminin/merosin binding and function as costimulatory molecules for human thymocyte proliferation.

Integrins comprise a superfamily of alpha beta heterodimers that serve as cell signaling as well as adhesion molecules. We demonstrate that the alpha 3 beta 1 and alpha 6 beta 1 integrins are laminin/merosin receptors expressed in human thymocytes. By reverse transcriptase-PCR analysis, we determined that the alpha 3A beta 1, but not the alpha 3B beta 1, cytoplasmic structural variant of alpha 3 beta 1 is expressed in thymocytes. In contrast, both alpha 6A beta 1 and alpha 6B beta 1 cytoplasmic structural variants of alpha 6 beta 1 are expressed. A small percentage (10 to 15%) of human thymocytes bind to immobilized laminin, and even fewer (3 to 5%) bind to merosin, the laminin isoform normally present in the thymus. This binding, however, can be increased to 39 to 41% after activation of thymocytes with Mn2+ (or PMA). Binding to either laminin or merosin is completely inhibited by anti-beta 1 mAb or by a mixture of anti-alpha 3 and anti-alpha 6 mAbs, indicating that both alpha 3 beta 1 and alpha 6 beta 1 participate in thymocyte adhesion to the laminin family of extracellular matrix proteins. The protein kinase C inhibitors, calphostin C and staurosporine, inhibit Mn(2+)-enhanced thymocyte binding, suggesting that protein kinase C activity is crucial for the binding. Furthermore, the data indicate that at least two divalent cation binding sites serve to regulate integrin binding activity. Finally, we show that both immobilized laminin and merosin have costimulatory function for anti-CD3-induced thymocyte proliferation, and both anti-alpha 3 and anti-alpha 6 mAbs can block this proliferative response. The cooperative function of alpha 3 beta 1 and alpha 6 beta 1 evidenced in the laminin/merosin binding and proliferation assays suggests that thymocyte-merosin interactions may play an important role in thymic T cell development.

Base Sequence↗

PubMed1994

[The relation between integrin, type IV collagenase and extracellular matrix in invasion and metastasis of gastric carcinoma].

The expression of integrin Alpha-6-subunit, laminin, type IV collagenase, type IV collagen and ras p21 were studied immunohistochemically in gastric cancer. The results showed that the expression of alpha 6 and laminin (LN) was often in continuous or interrupted linear pattern in the expanding type of gastric carcinoma (GC); while in the infiltrating type of GC, they were expressed either in interrupted spotty or fragmentary pattern, or almost lost. Suggesting that the interaction between the laminin receptor and its ligand may influence the mode of growth in GC. Intense expression of type IV collagenase was often found in GC cells, especially in the infiltrative type of GC and in those with lymph node metastasis, it can therefore be used as a marker for invasion and metastasis of GC cells. A positive correlation was found between the expression of type IV collagenase and ras p21 in GC. The expression of type IV collagen was similar to that of laminin, but in reverse proportion to the expression of type IV collagenase. These investigations provide a better understanding of the molecular pathological basis of tumor invasion and metastasis.

Breathing Exercises↗

PubMed1994

Differential expression of extracellular matrix molecules and the alpha 6-integrins in the normal and neoplastic prostate.

The epithelial basal lamina composition and integrin expression profile of normal and neoplastic human prostate was characterized using immunohistochemical analysis of frozen samples. The major components of the basal lamina surrounding normal acini were laminin, type IV collagen, entactin, and type VII collagen with variable amounts of tenascin. The basal lamina of neoplastic acini had a similar composition, except for the loss of type VII collagen, which was observed in all grades of carcinoma. The basal cells of the normal prostate express the alpha 6-, beta 1-, and beta 4-integrin subunits, suggesting that both the alpha 6 beta 1- and alpha 6 beta 4-integrin complexes are formed. In prostate carcinoma there is a complete loss of beta 4 expression and the alpha 6- and beta 1-integrin subunits, which are restricted to the basal and basal lateral surfaces of basal cells, are distributed diffusely throughout the cytoplasmic membrane. The differential expression of type VII collagen and beta 4 are discussed in relationship to their possible role in tumor progression.

Aged↗

PubMed1994

The integrin chains beta 1 and alpha 6 associate with the chaperone calnexin prior to integrin assembly.

Integrins are alpha beta heterodimers that mediate cell-cell adhesion, as well as cell-substrate adhesion. The largest subclass is formed by 10 heterodimers (the very late antigens) that all share the beta 1-chain. We have found a 90-kDa protein that co-isolates with mouse integrin beta 1-chain. This 90-kDa protein was identified as the mouse homolog of calnexin, a membrane-bound chaperone and resident protein of the endoplasmic reticulum. First, the sequence of the 15 NH2-terminal amino acids of the 90-kDa protein is 80% and 87% identical to the corresponding sequences of canine and human calnexin, respectively. Second, the 90-kDa protein was recognized by a monoclonal antibody against calnexin/IP90. Association of calnexin with the integrin beta 1-chain was directly demonstrated by chemical cross-linking. As pulse-chase experiments revealed, the association of the beta 1-chain with calnexin occurred prior to the assembly with integrin alpha 6-chain. Additionally, the alpha 6-chain bound to calnexin before integrin assembly and dissociated again at the time of integrin-assembly. Our data suggest that calnexin is involved in the assembly of beta 1 integrins, as well as in the retention of a pool of immature integrin beta 1-chains in the ER.

Amino Acid Sequence↗

PubMed1993

Expression of a functional laminin receptor (alpha 6 beta 1, very late activation antigen-6) on human eosinophils.

The mechanisms responsible for the accumulation of eosinophils at sites of allergic and other inflammatory reactions are unknown, but recent studies have implicated both eosinophil and endothelial adhesion molecules in this process. However, less well studied have been the adhesive interactions between eosinophils and the subendothelial basement membrane and interstitial connective tissues. To test the hypothesis that eosinophils might interact with extracellular matrix proteins, we analyzed purified human eosinophils for the expression and function of various beta 1 integrins. Using indirect immunofluorescence and flow cytometry, purified eosinophils from mildly allergic donors were found to consistently express the integrin subunits beta 1 (CD29), alpha 4 (CD49d, very late activation antigen [VLA]-4 alpha), and alpha 6 (CD49f, VLA-6 alpha). No significant expression of the alpha 1, alpha 2, alpha 3, alpha 5, or beta 4 subunits was detected. Platelet contamination of the eosinophil preparations was excluded by light microscopy and by the inability to detect expression of platelet glycoproteins alpha v, CD41b, and CD42b. Immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of eosinophils confirmed the expression of cell-surface beta 1, alpha 4, and alpha 6. Furthermore, eosinophils purified from allergic donors were shown to adhere to plate-bound laminin, but not to type 1 or type 4 collagen. Adhesion to laminin was concentration-dependent, required divalent cations, and was completely and specifically inhibited by the anti-alpha 6 monoclonal antibody (MoAb) GoH3 and by the anti-beta 1 MoAb 33B6. Interestingly, the anti-beta 1 MoAb 18D3 (which like 33B6 blocks eosinophil binding to VCAM-1) did not inhibit eosinophil adhesion to laminin, suggesting that there are functionally distinct epitopes on the beta 1 subunit. Eosinophils purified from 4 healthy, nonallergic donors also showed alpha 6-dependent adhesion to laminin, although these cells adhered less well. These studies establish the expression of alpha 6 beta 1 on human eosinophils and document its function as a laminin receptor. Interaction of eosinophil alpha 6 beta 1 with laminin, eg, in basement membranes, may contribute to the localization of these cells at inflammatory sites in vivo.

Animals↗

PubMed1995

VLA-6 (CDw49f) is an important adhesion molecule in NK cell-mediated cytotoxicity following autologous or allogeneic bone marrow transplantation.

Graft-vs.-leukemia (GVL) is postulated to be the principal mechanism responsible for continued remission after allogeneic bone marrow transplantation (BMT). The specific cytotoxic effectors mediating this effect are as yet undefined, but the major histocompatibility complex (MHC)-nonrestricted lysis of tumor cell lines by natural killer (NK) and lymphokine-activated killer (LAK) cells from recipients of allogeneic BMTs has been proposed as an in vitro correlate of GVL. In vitro culture or treatment in vivo with interleukin-2 (IL-2) is associated with enhanced NK cytotoxicity and lysis of NK-resistant targets (LAK cytotoxicity). NK, LAK, and cytotoxic T lymphocytes (CTL) have cytotoxic properties against autologous and allogeneic leukemic targets. These immune effector cells require receptor-ligand interaction for target recognition and adhesion via specific molecules such as integrins, a group of heterodimeric transmembrane glycoproteins. The integrins include the very late activation (VLA) subfamily, which all share the same beta 1 subunit but have distinct chains. VLA-6 (CDw49f) has been identified on NK cells and binds to laminin, a basement membrane protein found on malignant tumor cells but not normal cells. Monoclonal antibodies (mAbs) to laminin have been found to inhibit in vitro cytotoxicity of the tumor cell line K562, suggesting an important role for VLA-6 in this interaction. The specific aim of this study was to investigate the role of VLA-6 in the interactions of the tumor cell lines K562 and Daudi with peripheral blood lymphocytes (PBL) acting as effectors in cell-mediated cytotoxicity from normal volunteers, patients recovering from chemotherapy, and patients recovering from autologous or allogeneic BMT. In over 96% of assays, incubation of effector cells with anti-CDw49f mAbs led to detectable inhibition of NK and LAK cell-mediated cytotoxicity. More notably, the degree of anti-VLA6-induced suppression of LAK activity was significantly greater in the normal donors than in any of the patient groups, despite a significantly lower incidence of expression of VLA-6 on NK cells from controls than from patients. This implies a reduced role for this adhesion molecule in LAK activity following some form of in vivo stimulation. This hypothesis is supported by the observation that addition of exogenous IL-2 to the cultures ameliorated the effect of VLA-6 blockade, although the incidence and level of VLA-6 expression was unchanged by IL-2. In contrast, VLA-6 blocking led to a greater reduction in NK activity of BMT recipients than of normal donors, demonstrating that the VLA-6 adhesion pathway is important in this group of patients. These results indicate that the VLA-6-laminin interaction is important in normal NK-target interaction but may play a less significant role in the innate cytotoxic response post-BMT, perhaps reflecting subtle differences in the subsets of NK cells present in BMT recipients compared with normal donors.

Antibodies, Monoclonal↗

PubMed1996

Stimulation of tyrosine phosphorylation after ligation of beta7 and beta1 integrins on human B cells.

B lymphocytes express several members of the integrin family of adhesion molecules that mediate cell-cell and cell-extracellular matrix interactions. In addition to beta1 integrins, predominantly alpha4 beta1, mature B cells also express alpha4 beta7, which is a receptor for vascular cell adhesion molecule-1 and fibronectin, and is also involved in the homing of B cells to mucosal sites through binding to a third ligand, mucosal address in cell adhesion molecule-1. Here we describe that crosslinking of alpha4 beta7 integrins on B cell lines and normal tonsillar B cells, induces tyrosine phosphorylation of multiple substrates of 105-130 kD, indicating that beta7 integrin plays a role as signaling molecule in B cells. This pattern of phosphorylated proteins was very similar to that induced following ligation of alpha4 beta1. Interestingly, ligation of alpha5 beta1 or alpha6 beta1 also stimulated the 105-125 kD group of phosphorylated proteins, whereas ligation of beta2 integrins did not. The focal adhesion tyrosine kinase p125FAK was identified as one of these substrates. Beta1 or beta7 mediated tyrosine phosphorylations were markedly decreased when the microfilament assembly was inhibited by cytochalasin B. These results suggest that intracellular signals initiated by different integrins in B cells may converge, to similar cytoskeleton-dependent tyrosine phosphorylated proteins.

Antibodies, Monoclonal↗

PubMed1996

Function of the integrin alpha 6 beta 1 in metastatic breast carcinoma cells assessed by expression of a dominant-negative receptor.

The involvement of the alpha 6 beta a integrin, a laminin receptor, in breast carcinoma progression needs to be addressed rigorously. We report that a human breast carcinoma cell line, MDA-MB-435, known to be highly invasive and metastatic, expresses three potential integrin laminin receptors: alpha 2 beta 1, alpha 3 beta 1, and alpha 6 beta 1, but uses only alpha 6 beta 1 to mediate adhesion and migration on laminin matrices. To investigate the contribution of alpha 6 beta 1 to the aggressive behavior of these cells, we developed a dominant-negative strategy for knocking out alpha 6 beta 1 function that involved expression of a cytoplasmic domain deletion mutant of the beta 4 integrin subunit by cDNA transfection. Stable transfectants of MDA-MB-435 cells that expressed this mutant beta 4 subunit were inhibited dramatically in their ability to adhere and migrate on laminin matrices, and their capacity to invade Matrigel was reduced significantly. These findings support the hypothesis that alpha 6 beta 1 is important for breast cancer progression. Moreover, this approach is a powerful method that should be useful in assessing the role of alpha 6 beta 1 in other cells.

Breast Neoplasms↗

PubMed1996

Characterization of cell surface-expressed proteochondroitin sulfate of pre-B Nalm-6 cells and its possible role in laminin adhesion.

Cell surface-expressed proteoglycans mediate contacts to extracellular matrix (ECM). Human B lymphocytes produce a species of a proteochondroitin sulfate (CSPG) with an approximate molecular mass of 135-150 kDa. Using a monoclonal antibody (mAb) against B cell CSPG in flow cytometry we found that this CSPG is expressed on tumor cells of patients with CD19+ common acute lymphoblastic leukemia and on the corresponding cell lines Nalm-6, Reh and KM3. The CSPG is also present on hairy cell leukemia JOK-1 cells and weakly on the myeloma line U266. Concomitant with CSPG expression, Nalm-6 cells express the integrins alpha 5/beta 1 (CD49e/CD29) and alpha 6/beta 1 (CD49f/CD29), adhesion receptors for fibronectin and laminin, in contrast to the other two cell lines tested. Expression patterns of these adhesion receptors and CSPG were paralleled by strong adhesion of Nalm-6 to fibronectin and laminin. Adhesion of Nalm-6 to fibronectin was inhibited by the alpha 5-specific antibody SAM 1 by 80% whereas the alpha 6-specific antibody GoH3 reduced binding to laminin only by 20%. A possible involvement of surface-expressed CSPG in adhesion to ECM components was investigated by 24 h incubation of Nalm-6 cells with p-nitrophenyl-beta-D-xyloside, an inhibitor of proteoglycan glycosylation. By this treatment, both adhesion of Nalm-6 to laminin and expression of CSPG were reduced by 40-50%. Furthermore, addition of chondroitin-6-sulfate, a structural element of Nalm-6 CSPG, reduced adhesion of Nalm-6 to laminin by 60%. Chondroitin-4-sulfate, heparin and heparan sulfate did not effectively inhibit the adhesion process. These observations suggest that surface-expressed CSPG may be involved in binding of Nalm-6 cells to laminin and that the specific sulfation pattern of chondroitin-6-sulfate may be essential in this regard.

Antigens, CD↗

PubMed1996

Altered integrin expression in rheumatoid synovial lining type B cells: in vitro cytokine regulation of alpha 1 beta 1, alpha 6 beta 1, and alpha v beta 5 integrins.

OBJECTIVE: We recently showed that in rheumatoid arthritis (RA) the extracellular matrix around the lining cells is similar to the matrix seen in osteoarthritis, whereas the cellular adhesion apparatus is very different. In hyperplastic synovial membrane there is very little of alpha 6, alpha v, and beta 5 integrin subunits, whereas in noninflammatory synovial membrane these integrins are well expressed. We studied how expression of these cell adhesion molecules is regulated in RA in vitro. METHODS: The integrin expression in 6 different synovial fibroblast strains representing the type B cells and in THP-1 cell line was examined by immunoprecipitation, flow cytometry, and Northern hybridization. RESULTS: Proinflammatory cytokines, especially interleukin 1 beta, increased the expression of alpha 1 integrin in synovial fibroblasts. When the monocyte-like THP-1 cells were induced to differentiate to adherent macrophages they started to express alpha 6 and beta 5 integrin subunits. In adherent THP-1 cells the expression of integrin alpha 6 subunit was strongly enhanced by transforming growth factor-beta and downregulated by the combination of tumor necrosis factor-alpha and interferon-gamma. CONCLUSION: Cytokines regulate the cell adhesion molecules of synovial fibroblasts and mononuclear phagocytes in vitro causing alterations in integrin expression similar to the ones seen in rheumatoid synovium in vivo.

Adult↗

PubMed1996

A role in migration for the alpha V beta 1 integrin expressed on oligodendrocyte precursors.

Myelination of the CNS requires the migration of oligodendrocyte precursors throughout the CNS from restricted regions within the ventricular and subventricular zones. In light of the significant effects of cell-extracellular matrix (ECM) interactions on cell migration in other developing systems, we have analyzed the role of integrins in oligodendrocyte precursor migration. We have shown previously that oligodendrocyte precursors in vitro express a limited repertoire of integrins, including alpha 6 beta 1, alpha v beta 3, and that differentiation is associated with downregulation of alpha v beta 1 and upregulation of alpha v beta 5. Using a migration assay based on the movement of cells away from an agarose drop containing a high-density cell suspension, we find that RGD peptides (that block alpha v but not alpha 6 integrins) and anti-beta 1 antibodies block migration on an astrocyte-derived ECM, whereas anti-beta 3 antibodies have little effect. These results suggest that alpha v beta 1 but not alpha 6 beta 1 plays a role in oligodendrocyte precursor migration, and this is confirmed by the use of blocking monoclonal antibodies that distinguish these two integrins. In keeping with the results of others, we find that differentiated oligodendrocytes lose migratory potential and that the timing of this loss correlates with downregulation of alpha v beta 1. Taken together with the work of others showing that ECM ligands for alpha v beta 1 are expressed within the CNS, we propose that this integrin plays a significant role in the migration of oligodendrocyte precursors in vivo and that its downregulation during differentiation could be an important factor regulating the migratory phenotype of these cells.

Animals↗

PubMed1997

Distinct changes in the laminin composition of basement membranes in human seminiferous tubules during development and degeneration.

We studied the distribution of laminin (Ln) chains and their integrin (Int) receptors in normal developing and adult and in atrophied human testes by using immunohistochemistry. Immunostaining for EHS Ln and type IV collagen was used to identify basement membranes (BMs). In the BM of seminiferous epithelium of fetal testis, a panel of monoclonal antibodies showed immunoreactivity for Ln alpha 1-, alpha 2-, beta 1-, beta 2- and gamma 1-chains, suggestive of the presence of Lns 1 to 3. In BM of adult seminiferous epithelium with active spermatogenesis, immunoreactivity for Ln beta 2- and gamma 1-chains was found but not for Ln alpha-chains, suggesting a complex of Ln chains not compatible with any known trimers. Instead, with polyclonal Ln antiserum and monoclonal antibody to type IV collagen, a distinct BM-like reactivity was seen. In atrophied testes, prominent immunoreactivities for Ln chains, compatible with Lns 1 to 3, were seen in the thickened BM of seminiferous tubules, hence suggestive of reappearance of fetal Lns. Among the subunits of Ln-binding Int receptors in fetal seminiferous tubules, a strong immunoreactivity for Int beta 1- and Int alpha 6-subunits was seen throughout the seminiferous epithelium, other Int subunits being found in interstitial cells. In the adult and atrophied testes, immunoreactivities for Int beta 1- and Int alpha 6-subunits were seen to be confined to the basal aspect of the seminiferous epithelium whereas immunoreactivities for Int alpha 1-, alpha 2-, alpha 3- and beta 4-subunits were seen in the myoid cells. The results show that both maturation and degenerative changes of human testes are accompanied by distinct changes in the Ln expression of BM of seminiferous epithelium, which appears to accompany epithelial differentiation of the Sertoli cells. Furthermore, they suggest the presence of a novel Ln trimer in BM of adult human seminiferous tubules.

Adult↗

PubMed1997

Adult Schistosoma mansoni worms positively modulate soluble egg antigen-induced inflammatory hepatic granuloma formation in vivo. Stereological analysis and immunophenotyping of extracellular matrix proteins, adhesion molecules, and chemokines.

Synchronized liver granulomas were induced by injecting Sepharose beads to which SEA soluble egg antigen (SEA) or the concanavalin A binding fraction of SEA had been coupled into a mesenteric vein in naive, single-sex (35 days) and bisexually (28 days) Schistosoma mansoni-infected and Plasmodium berghei-immunized mice. Stereological analysis revealed that peak granuloma formation was already reached 8 days after injection in single-sex infected mice compared with 16 days in naive animals. No difference in granuloma formation between naive and P. berghei-immunized animals and between unisexually and bisexually S. mansoni-infected mice was observed. This suggests that the positive immunomodulatory effect on the granulomogenesis is worm specific and not likely to be due to arousal of the immune system by unrelated factors, nor is it influenced by the gender or degree of maturation of female worms. At all stages in time, the concanavalin A binding-fraction-induced granulomas reached only 65 to 70% of the volume of SEA-induced granulomas. Immunophenotyping of extracellular matrix proteins around deposited heads revealed that fibronectin was the dominant extracellular matrix protein and that also type I and IV collagen and laminin were deposited. Temporal analysis of the expression of the adhesion molecules ICAM-1, LFA-1, VLA-4, and VLA-6 was performed. Morphological evidence is presented for the role of adhesion molecules in the initiation and maintenance of hepatic granuloma formation. The chemokine monocyte chemoattractant protein-1 was expressed in the granuloma and in hepatic artery branches. From these data, it is concluded that adult S. mansoni worms positively modulate schistosomal hepatic granuloma formation in vivo. Adhesion molecules and chemokines play important roles in schistosomal granuloma formation.

Animals↗