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PubMed1996

The specificity of adhesive interactions between rat lymphocytes and salivary gland epithelia.

Salivary immune responses depend on localization of immunocytes in salivary glands. We tested effects of anti-adhesion molecule antibodies and several ligand analogs on in vitro adherence of rat thoracic duct lymphocytes (TDL) to parotid and submandibular gland sections. While TDL adherence to both tissues was markedly decreased by anti-L-selectin mAbs, binding ability after removal of L-selectin by chymotrypsin or PMA suggested that other adhesion systems were involved. Integrin involvement in parotid interactions was indicated by inhibitory effects of anti-HEBF(PP), LFA-1, ICAM-1, and alpha4 integrin antibodies as well as by the PMA-enhanced adherence. Anti-Thy-1 partially inhibited TDL binding to parotid gland, and anti-CD44 partially inhibited submandibular binding. The majority of salivary gland-bound TDL were sIg+ B cells. FACS analysis showed differences in parotid and submandibular endogenous lymphocyte adhesion molecule expression with greater percentages of L-selectin, HEBF(PP), alpha4 integrin, LFA-1, ICAM-1, CD44, and Thy-1-positive cells present in parotid gland. While precise roles of known or novel adhesion molecules in salivary gland lymphocyte retention are not clear, these data suggest that selectins (parotid, submandibular), integrins (parotid), Thy-1 (parotid), and CD-44 (submandibular), as well as other unidentified molecules, are involved.

Animals↗

PubMed1998

The C-C chemokine receptor CCR3 participates in stimulation of eosinophil arrest on inflammatory endothelium in shear flow.

Chemokines are widely hypothesized to stimulate firm adhesion of leukocytes on endothelium in shear flow. Thus far, this has been demonstrated experimentally for exogenously added chemoattractants, but not for those released by endothelium. We found that human umbilical cord endothelial cells (HUVEC) stimulated with TNF-alpha and IFN-gamma secreted eosinophil chemoattractants into the culture supernatant. This material induced transendothelial chemotaxis, stimulated eosinophil binding to purified intercellular adhesion molecule 1, and augmented binding to purified vascular cell adhesion molecule 1 in a 3-min static assay. Chemotaxis and stimulation of adhesion were abrogated completely by the pretreatment of eosinophils with an mAb to the C-C chemokine receptor 3 (CCR3). Eosinophils accumulated efficiently on HUVEC stimulated with TNF-alpha and IFN-gamma in shear flow at 1.5 dyn/cm2. CCR3 mAb slightly but significantly reduced eosinophil arrest and accumulation, by preventing development of firm adhesion by some of the tethered eosinophils, so that they detached within 30 s after the initial tethering. In the presence of mAb to the alpha4 integrin subunit, the effect of CCR3 mAb was more prominent, and approximately half of eosinophil arrest and accumulation was abolished. Inhibition by CCR3 mAb in the presence of beta2 integrin mAb was similar to that in control eosinophils. This is the first evidence that endothelial cell-derived chemokines can activate firm adhesion through alpha4 and beta2 integrins even in the presence of shear flow.

Antigens, CD↗

PubMed2005

Effect of phase limited inhibition of MyoD expression on the terminal differentiation of bovine myoblasts: no alteration of Myf5 or myogenin expression.

To investigate the roles played by MyoD in the terminal differentiation of satellite cell-derived myoblasts, the effect of antisense inhibition of MyoD expression was examined in bovine adult myoblast culture, in which inhibition treatment was limited to the terminal differentiation phase. MyoD antisense oligonucleotide DNA (AS-mD) suppressed the formation of multinucleated myotubes in the cell culture. Myotube formation was suppressed even when AS-mD treatment was limited to the period preceding the onset of myotube formation. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis revealed that treatment with AS-mD suppressed the expression of myosin heavy chain embryonic isoform and troponin T isoforms at 4 days after the induction of differentiation. AS-mD also suppressed the expression of MRF4, but did not alter the expression of either Myf5 or myogenin, in contrast to previous results using mouse cells possessing MyoD(-/-) genetic background. These findings suggest that MyoD controls myogenesis but not Myf5 or myogenin mRNA expression during the terminal differentiation phase. Furthermore, among the alpha4, alpha5, alpha6, and alpha7 integrins, alpha4, alpha5, and alpha7 integrin expression was suppressed by AS-mD treatment, in parallel with the suppression of myotube formation, which suggests that MyoD controls myotube formation by regulating the expression of alpha4, alpha5, and alpha7 integrins.

Animals↗

PubMed2001

Blockade of either alpha-4 or beta-7 integrins selectively inhibits intestinal mast cell hyperplasia and worm expulsion in response to Nippostrongylus brasiliensis infection.

Mast cells are known to express high levels of alpha4 integrins including alpha4beta7 and are found in increased numbers in mucosal inflammation. Mast cell accumulation is particularly prominent in the intestine following nematode infection. The adhesion molecule requirements for this process have not yet been defined. The role of alpha4 and beta7 integrin chains in the intestinal mast cell hyperplasia following infection of rats with the nematode parasite Nippostrongylus brasiliensis was examined in this study. Rats were infected with N. brasiliensis larvae and treated with either anti-alpha4 (TA-2), anti-beta7 or isotype-matched control antibodies. The initial mast cell hyperplasia in response to N. brasiliensis infection was significantly inhibited by either anti-alpha4 or anti-beta7 treatment. In contrast, the intestinal eosinophil response to N. brasiliensis infection was not reduced at day 14 or day 16. Elevations in serum IgE levels due to N. brasiliensis infection were also not inhibited by anti-alpha4 or anti-beta7 antibody treatment. Anti-alpha4 antibody but not anti-beta7 antibody treatment also induced a small but significant decrease in the numbers of mast cells in tongue tissue. These data suggest a role for alpha4 integrins, in particular alpha4beta7, in the regulation of mast cell precursor migration to the intestine.

Animals↗

PubMed1997

Molecular mechanisms of monocyte adhesion to interleukin-1beta-stimulated endothelial cells under physiologic flow conditions.

This study identifies multiple pathways used by monocytes to adhere to 4-hour interleukin-1beta stimulated human umbilical vein endothelial cells under flow conditions. Physiologic shear stresses were simulated in a flow chamber with parallel plate geometry; quantitation of primary adhesion, secondary adhesion, and transmigration was performed using phase contrast videomicroscopy. Neuraminidase treatment of monocytes reduced primary interaction by 50%, whereas blocking L-selectin or very late antigen-4 showed significant but smaller effects (approximately 30% inhibition). However, a combined treatment against all three pathways was able to reduce interaction by 80%. Blocking beta2 and alpha4 integrin pathways together inhibited secondary/firm adhesion by 75%. Only 40% of firmly adherent monocytes transmigrated across the endothelial monolayer with significantly increased transmigration times when both beta2 and alpha4 integrins were blocked. These results demonstrate that monocytes can use multiple receptors to interact with endothelial cells at both primary and secondary adhesion stages, and that these pathways have to be blocked simultaneously for maximum inhibition.

Cell Adhesion↗

PubMed1998

Differential regulation of eosinophil adhesion and transmigration by pulmonary microvascular endothelial cells.

In bronchial asthma, eosinophils (EOS) adhere to, and migrate across, the lung microvasculature to exert their effector functions in the airways. This study was conducted to determine the effect of cytokines on adhesion molecule expression on human pulmonary microvascular endothelial cells (HPMEC) and the influence of these molecules on EOS adhesion and transmigration in vitro. Unlike ICAM-1 expression (>80% positive cytokine-treated HPMEC by flow cytometry), VCAM-1 expression varied with the cytokine(s) pretreatment; the order of potency was: TNF-alpha + IL-4 (82.2 +/- 4.2% positive cells) > TNF-alpha (41.8 +/- 5.1%) > IL-1beta (20.8 +/- 4.7%). IL-4 alone had no effect on either ICAM-1 or VCAM-1 expression. EOS adhesion to cytokine-treated HPMEC followed the same order as that observed for VCAM-1 expression. Interestingly, EOS migration across cytokine-treated HPMEC varied inversely with VCAM-1 expression on, and EOS adhesion to, HPMEC; IL-1beta (21.2 +/- 1.4% migration) > TNF-alpha (12.6 +/- 2.6%) > TNF-alpha + IL-4 (9.1 +/- 2.0%). EOS adhesion was greatest with TNF-alpha + IL-4-treated HPMEC, was dependent on VCAM-1, and inhibited with anti-alpha4 integrin mAb (67.7 +/- 7.5% inhibition, p < 0.0005). In contrast, the highest EOS migration occurred across IL-1beta-treated HPMEC and was inhibited by anti-beta2 integrin mAb (40.4 +/- 2.5% inhibition, p < 0.005). Viable HPMEC were required for EOS migration but not adhesion. Our results suggest that EOS adhesion and transmigration are differentially regulated by VCAM-1 and ICAM-1 expression and the interaction of these adhesion proteins with their respective counterligands, i.e., alpha4 and beta2 integrins on EOS.

Adult↗

PubMed2003

A controlled trial of natalizumab for relapsing multiple sclerosis.

BACKGROUND: In patients with multiple sclerosis, inflammatory brain lesions appear to arise from autoimmune responses involving activated lymphocytes and monocytes. The glycoprotein alpha4 integrin is expressed on the surface of these cells and plays a critical part in their adhesion to the vascular endothelium and migration into the parenchyma. Natalizumab is an alpha4 integrin antagonist that reduced the development of brain lesions in experimental models and in a preliminary study of patients with multiple sclerosis. METHODS: In a randomized, double-blind trial, we randomly assigned a total of 213 patients with relapsing-remitting or relapsing secondary progressive multiple sclerosis to receive 3 mg of intravenous natalizumab per kilogram of body weight (68 patients), 6 mg per kilogram (74 patients), or placebo (71 patients) every 28 days for 6 months. The primary end point was the number of new brain lesions on monthly gadolinium-enhanced magnetic resonance imaging during the six-month treatment period. Clinical outcomes included relapses and self-reported well-being. RESULTS: There were marked reductions in the mean number of new lesions in both natalizumab groups: 9.6 per patient in the placebo group, as compared with 0.7 in the group given 3 mg of natalizumab per kilogram (P<0.001) and 1.1 in the group given 6 mg of natalizumab per kilogram (P<0.001). Twenty-seven patients in the placebo group had relapses, as compared with 13 in the group given 3 mg of natalizumab per kilogram (P=0.02) and 14 in the group given 6 mg of natalizumab per kilogram (P=0.02). The placebo group reported a slight worsening in well-being (a mean decrease of 1.38 mm on a 100-mm visual-analogue scale), whereas the natalizumab groups reported an improvement (mean increase of 9.49 mm in the group given 3 mg of natalizumab per kilogram and 6.21 mm in the group given 6 mg of natalizumab per kilogram). CONCLUSIONS: In a placebo-controlled trial, treatment with natalizumab led to fewer inflammatory brain lesions and fewer relapses over a six-month period in patients with relapsing multiple sclerosis.

Adult↗

PubMed2002

Antiadhesion molecule therapy in inflammatory bowel disease.

Adhesion molecules regulate the influx of leukocytes in normal and inflamed gut. Some of these molecules such as MadCAM-1 are specific for the gastrointestinal endothelium, but in inflammatory bowel diseases most of the adhesion factors are up-regulated. Adhesion molecules also are involved in local lymphocyte stimulation and antigen presentation within the intestinal mucosa. Recently, therapeutic compounds directed against trafficking of lymphocytes toward the gut mucosa have been designed, and are being developed as a novel class of drugs in the treatment of Crohn's disease (CD) and ulcerative colitis. This review deals with the immunological aspects of leukocyte trafficking focused on gut homing of T cells. Secondly, the changes in adhesion molecules and T-cell trafficking during intestinal inflammation are discussed. Finally, we review the clinical data that have been gathered in trials of biological therapies directed against adhesion molecules. Both antiintercellular adhesion molecule-1 (ICAM-1) and anti-alpha4 integrin strategies are being developed. Trials with the anti-ICAM-1 antisense oligonucleotide, ISIS-2302, in steroid-refractory CD have provided conflicting efficacy data. The anti-alpha4 integrin antibodies natalizumab (Antegren) and LDP-02 are in phase III and phase II trials, respectively. In the near future, these novel biological agents may prove valuable therapeutic tools in the management of refractory IBD.

Antibodies↗

PubMed2000

Infusion of an antialpha4 integrin antibody is associated with less neoadventitial formation after balloon injury of porcine coronary arteries.

BACKGROUND: The alpha4beta1 (or very late antigen-4 [VLA-4]) integrin is thought to play a role in inflammatory processes, mediating mononuclear leukocyte infiltration. The adventitial response to balloon injury is an important determinant of neointimal formation and arterial remodelling. OBJECTIVES: To determine whether the monoclonal antibody hHP1/2 directed against the human alpha4-integrin subunit decreases neoadventitial formation and subsequent luminal narrowing following balloon injury. DESIGN: Randomized, double-blind, placebo controlled study. SETTING: Tertiary care, Canadian university hospital vascular biology laboratory. ANIMALS AND METHODS: In 16 pigs, two coronary arteries were injured with an oversized balloon, while a third coronary artery was designated as an uninjured control vessel. One hour before balloon injury, 5 mg/kg of hHP1/2 was administered to eight animals, while another eight animals received an infusion of a saline placebo. Animals were killed three and 14 days following balloon injury. MAIN RESULTS: Administration of hHP1/2 resulted in an immediate decrease in circulating monocyte and lymphocyte counts. These parameters returned to normal within three days. There was a decrease in neoadventitial formation 14 days after arterial injury in pigs treated with hHP1/2 compared with controls (2.26+/-0.77 versus 3.42+/-1.01 mm, respectively, P=0.04). There was a loss of lumen area between days 3 (4.33+/-1.09 mm2) and 14 (3.09+/-0.38 mm2, P=0.02) after balloon injury in pigs treated with saline, but not in the pigs treated with hHP1/2. CONCLUSIONS: Administration of an antibody to the alpha4-integrin subunit is associated with less neoadventitial formation and less lumenal narrowing after balloon injury. This novel therapy may play an important role in modulating arterial remodelling and thereby may reduce restenosis following percutaneous coronary interventions in humans.

Angioplasty, Balloon, Coronary↗

PubMed1998

The response of periodontal ligament cells to fibronectin.

Fibronectin (fn) is an extracellular matrix (ECM) molecule important in cell adhesion and migration and in wound healing. It is also likely important in periodontal ligament (PDL) cell-ECM interactions, and thus in regenerating periodontal tissues. In this study we characterized PDL cells and their interactions with FN, testing different PDL cell isolates taken from healthy and diseased conditions. PDL cells were characterized by their morphology, integrin profile, motility, and bone nodule formation. Cells were then assayed for adhesion, proliferation, and chemotaxis in response to FN or FN fragments. Cell isolates were morphologically heterogeneous and fibroblastic, had a normal-appearing actin cytoskeleton and a wide range of migration potentials, and formed bone-like nodules in vitro. They expressed alpha5, beta1, alpha v, and alpha4 integrin subunits, known receptors for FN, and in fact they bound FN preferentially at 5 and 10 microg/ml. Intact FN induced greater PDL cell proliferation and chemotaxis than did FN fragments (120-kDa cell-binding, 60-kDa heparin-binding, and 45-kDa collagen-binding). PDL cells harvested from diseased and healthy conditions were no different on the basis of these assays. These data demonstrate that PDL cells are a mixed population of fibroblastic cells, capable of forming a mineralized matrix. They also suggest that maximal proliferation and chemotaxis require specific FN domains that are present on the intact molecule but not its fragments.

Actins↗

PubMed1999

P-selectin binding promotes the adhesion of monocytes to VCAM-1 under flow conditions.

This study examined the adhesive interaction of peripheral blood monocytes with VCAM-1 and analyzed the effect of P-selectin binding to monocytes on the adhesive interaction with VCAM-1 under flow conditions. P-selectin glycoprotein ligand-1 is expressed on most monocytes. Furthermore, most monocytes bind soluble P-selectin derived from platelets. P-selectin binding to monocytes did not alter the amount of expression of alpha4 integrin on monocytes. However, the mean channel fluorescence value for binding Cy2-conjugated soluble VCAM-1 to P-selectin-bound monocytes was slightly more than that for binding Cy2-conjugated soluble VCAM-1 to untreated monocytes. Under flow conditions, the number of P-selectin-bound monocytes bound to VCAM-1 was much higher than that of untreated monocytes bound to VCAM-1. These bindings were abolished by pretreatment of untreated monocytes and P-selectin-bound monocytes with anti-VCAM-1 mAb or anti-alpha4 integrin mAb. Furthermore, P-selectin binding to monocytes increased shear resistance and thus increased the adhesive strength of monocytes to VCAM-1. These findings indicate that P-selectin binding to monocytes enhances the adhesive interaction of monocytes with VCAM-1. It is suggested that P-selectin glycoprotein ligand-1/P-selectin interaction and alpha4 integrin/VCAM-1 interaction can act sequentially in the adhesion cascade that regulates monocyte trafficking to inflammatory and atherosclerotic lesion.

Blood Flow Velocity↗

PubMed2006

Immunoscreening of a cutaneous T-cell lymphoma library for plasma membrane proteins.

Cutaneous T-cell lymphomas (CTCL) belong to non-Hodgkin lymphomas, which are primarily manifested in the skin and mostly exhibit a T-helper memory phenotype. Mycosis fungoides (MF) and the leukemic variant Sézary syndrome (SzS) are the most common forms of CTCL. The aim of this study was to identify CTCL surface proteins with a tumor specific expression profile. A plasma membrane enriched fraction of the CTCL cell line HuT78 was used for immunization of two rabbits. Subsequently, a CTCL cDNA phage library was screened by a new variant of the SEREX method (serological identification of antigens by recombinant expression cloning) using the polyspecific rabbit antisera instead of patients' sera. Isolated reactive transfectants were sequenced and 42 different genes identified including four known plasma membrane proteins: Ligatin, HLA-A, integrin alpha4 and MT5-MMP. The level of transcripts of the matrix metalloproteinase MT5-MMP was diminished in MF tumor specimens. MT5-MMP normally occurs in several different protein variants. Western blot analysis revealed that activated MT5-MMPs were reduced in tumor specimens, whereas the amounts of most of the inactivated variants were unchanged. The amount of mRNA coding for the adhesion protein integrin alpha4 was not altered in tumor specimens in comparison to controls when analyzed by quantitative real-time PCR analysis. Ku86, known to be predominantly located in the nucleus and cytosol, was frequently detected during the SEREX screening. Western blot analysis revealed higher protein amounts of Ku86 in HuT78 than in control cells. In addition, we could show, that Ku86 can also be detected in lipid rafts of CTCL cells as it has been described for other tumor types. Thus, Ku86 might be involved in homo- and heterotypic adhesion steps of CTCL tumor cells and might protect these cells against apoptosis triggered by irradiation as it was suggested for multiple myeloma cells. The design of this study enabled screening for all proteins on the plasma membrane, irrespectively of whether these are directly anchored within the membrane or associated with other membrane proteins. Further analysis will unravel whether the list of identified proteins harbors candidates, which might be accessible for antibodies from outside the cell.

Animals↗

PubMed2005

Invasive and noninvasive uveal melanomas have different adhesive properties.

AIMS: To establish if invasive and noninvasive uveal melanomas have differences in expression of adhesion molecules, and whether their adhesive interactions with the extracellular matrix (ECM) and endothelium vary. METHODS: Cells from an invasive and noninvasive uveal melanoma cell line and hepatic and dermal microvascular endothelial cells were assessed by flow cytometry for adhesion molecule expression. Tumour cell adhesion to ECM substrates (collagens I and IV, fibronectin, laminin, and vitronectin) and endothelial cells was also investigated using a commercially available assay or a fluorescence-based in vitro assay, respectively. The significance of results comparing cell lines was determined using a Student's t-test, whereby P-values of less than 0.05 were taken as significant. RESULTS: alpha1- and alpha4-integrins were not expressed by noninvasive cells, but were detected on invasive cells. The invasive cell line also expressed higher levels of other integrins than the noninvasive line. Correspondingly, invasive cells adhered in higher numbers to ECM substrates and endothelial cells, and for the latter, the difference was highly significant (P<0.001). No preference in adhesion of invasive cells for the hepatic endothelium was observed. CONCLUSIONS: Successful attachment to and migration through the ECM, basement membrane, and endothelium are vital processes involved in malignant progression. Differential expression of alpha1- and alpha4-integrins by invasive and noninvasive cells infers a role for these receptors in invasion, while the ability of invasive cells to adhere more efficiently to the endothelium suggests that this is a critical factor in uveal melanoma invasion.

Cell Adhesion↗

PubMed2000

CCR3-active chemokines promote rapid detachment of eosinophils from VCAM-1 in vitro.

Selective eosinophil recruitment is the result of orchestrated events involving cell adhesion molecules, chemokines, and their receptors. The mechanisms by which chemokines regulate eosinophil adhesion and migration via integrins are not fully understood. In our study, we examined the effect of CCR3-active chemokines on eosinophil adhesion to VCAM-1 and BSA under both static and flow conditions. When eotaxin-2 or other CCR3-active chemokines were added to adherent eosinophils, it induced rapid and sustained eosinophil detachment from VCAM-1 in a concentration-dependent manner. Adhesion was detectably reduced within 3 min and was further reduced at 10-60 min. Simultaneously, eotaxin-2 enhanced eosinophil adhesion to BSA. Preincubation of eosinophils with the CCR3-blocking mAb 7B11 completely prevented chemokine-induced changes in adhesion to VCAM-1 and BSA. Using a different protocol, pretreatment of eosinophils with chemokines for 0-30 min before their use in adhesion assays resulted in inhibition of VCAM-1 adhesion and enhancement of BSA adhesion. By flow cytometry, expression of alpha4 integrins and a beta1 integrin activation epitope on eosinophils was decreased by eotaxin-2. In a flow-based adhesion assay, eotaxin-2 reduced eosinophil accumulation and the strength of attachment to VCAM-1. These results show that eotaxin-2 rapidly reduced alpha4 integrin function while increasing beta2 integrin function. These findings suggest that chemokines facilitate migration of eosinophils by shifting usage away from beta1 integrins toward beta2 integrins.

Actins↗

PubMed2005

Differences in potency of CXC chemokine ligand 8-, CC chemokine ligand 11-, and C5a-induced modulation of integrin function on human eosinophils.

The hypothesis was tested that different chemoattractants have different effects on the activity of integrins expressed by the human eosinophil. Three chemoattractants, CXCL8 (IL-8), CCL11 (eotaxin-1), and C5a were tested with respect to their ability to induce migration and the transition of eosinophils from a rolling interaction to a firm arrest on activated endothelial cells under flow conditions. CCL11 and C5a induced a firm arrest of eosinophils rolling on an endothelial surface, whereas CXCL8 induced only a transient arrest of the cells. The CXCL8- and CCL11-induced arrest was inhibited by simultaneously blocking alpha4 integrins (HP2/1) and beta2 integrins (IB4). In contrast, the C5a-induced arrest was only inhibited by 30% under these conditions. The potency differences of C5a>CCL11>CXCL8 to induce firm adhesion under flow condition was also observed in migration assays and for the activation of the small GTPase Rap-1, which is an important signaling molecule in the inside-out regulation of integrins. Interestingly, only C5a was able to induce the high activation epitope of alphaMbeta2 integrin recognized by MoAb CBRM1/5. The C5a-induced appearance of this epitope and Rap activation was controlled by phospholipase C (PLC), as was shown with the PLC inhibitor U73122. These data show that different chemoattractants are able to induce distinct activation states of integrins on eosinophils and that optimal chemotaxis is associated with the high activation epitope of the alphaMbeta2 integrin. Furthermore, PLC plays an important role in the inside-out signaling and, thus, the activation status of integrins on eosinophils.

CD18 Antigens↗

PubMed1999

The integrin alpha9beta1 mediates adhesion to activated endothelial cells and transendothelial neutrophil migration through interaction with vascular cell adhesion molecule-1.

The integrin alpha9beta1 has been shown to be widely expressed on smooth muscle and epithelial cells, and to mediate adhesion to the extracellular matrix proteins osteopontin and tenascin-C. We have found that the peptide sequence this integrin recognizes in tenascin-C is highly homologous to the sequence recognized by the closely related integrin alpha4beta1, in the inducible endothelial ligand, vascular cell adhesion mole-cule-1 (VCAM-1). We therefore sought to determine whether alpha9beta1 also recognizes VCAM-1, and whether any such interaction would be biologically significant. In this report, we demonstrate that alpha9beta1 mediates stable cell adhesion to recombinant VCAM-1 and to VCAM-1 induced on human umbilical vein endothelial cells by tumor necrosis factor-alpha. Furthermore, we show that alpha9beta1 is highly and selectively expressed on neutrophils and is critical for neutrophil migration on VCAM-1 and tenascin-C. Finally, alpha9beta1 and alpha4 integrins contribute to neutrophil chemotaxis across activated endothelial monolayers. These observations suggest a possible role for alpha9beta1/VCAM-1 interactions in extravasation of neutrophils at sites of acute inflammation.

Animals↗

PubMed1997

Analysis of initial attachment of B cells to endothelial cells under flow conditions.

This study examined the adhesive interactions of peripheral blood B cells with TNF-alpha-activated endothelial monolayers, and analyzed the roles of E-selectin, P-selectin, or VCAM-1 molecules expressed on activated HUVEC. B cell interaction occurred on activated HUVEC, but not on resting HUVEC under flow conditions. The majority of peripheral blood B cells expressed P-selectin glycoprotein ligand-1 and alpha4 integrin. However, the expression of cutaneous lymphocyte Ag on B cells was low. Under flow conditions, B cells could bind to P-selectin-coated tubes and VCAM-1-transfected Chinese hamster ovary cells. In contrast, B cells could not bind to E-selectin-coated tubes. Adhesion activity of B cells to P-selectin-coated tubes was weaker than that of T cells. Furthermore, adhesion activity of B cells to VCAM-1-transfected Chinese hamster ovary cells was similar to that of T cells. Treatment of activated HUVEC with anti-VCAM-1 mAb reduced interaction of B cells under flow conditions. However, the treatment of activated HUVEC with anti-P-selectin mAb did not reduce interaction. These data indicated that the interaction of VCAM-1 with alpha4 integrin plays a major role in an initial attachment of B cells to endothelial monolayers under flow conditions.

Animals↗

PubMed2006

Antisense therapy of MAdCAM-1 for trinitrobenzenesulfonic acid-induced murine colitis.

BACKGROUND: Anti-alpha4 integrin reagent, natalizumab, which is 1 of the most promising antiadhesion monoclonal antibodies, has been introduced into clinical trials against inflammatory bowel disease (IBD). Lethal consequences such as progressive multifocal leukoencephalopathy have recently been reported in patients using natalizumab, making it critical to determine which selective adhesion molecule in the alpha4 integrins-dependent pathway should be targeted for inhibition and the minimal spectrum of activity required for the valid treatment of IBD. Mucosal addressin cell adhesion molecule (MAdCAM)-1 is known to be restrictedly expressed in gut-associated lymphoid tissues, and its expression dramatically increases in IBD. This study aimed to reevaluate the effectiveness of MAdCAM-1 inhibition and to determine the feasibility of anti-MAdCAM-1 strategy. MATERIALS AND METHODS: Antisense MAdCAM-1 oligonucleotides were injected into mice at 1.5 mg/kg/day for 7 consecutive days from the first day of a trinitrobenzene sulfonate enema. RESULTS: MAdCAM-1 antisense oligonucleotides significantly suppressed the development of trinitrobenzene sulfonate colitis clinically and histopathologically compared with controls. Immunohistochemistry and semiquantitative reverse-transcription polymerase chain reaction of the colon tissues revealed that MAdCAM-1 protein and mRNA expression were lower in antisense-treated mice than in controls. In addition, MAdCAM-1 antisense treatment reduced the number of alpha4beta7 lymphocytes in the inflamed colonic mucosa. CONCLUSIONS: These data suggest that antisense suppression of MAdCAM-1 is of equivalent effectiveness to that of anti-MAdCAM-1 or anti-alpha4 integrin antibody in previous reports and could be a new therapy for IBD.

Animals↗