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At least 19 recordsLinked to original sources
PubMed1988

Evidence that neutrophil accumulation induced by interleukin-1 requires both local protein biosynthesis and neutrophil CD18 antigen expression in vivo.

1. Mechanisms involved in neutrophil accumulation induced by intradermal injection of interleukin-1 (IL-1) in the rabbit were investigated using intravenously-injected 111In-labelled neutrophils. C5a des Arg, N-formyl-methionyl-leucyl-phenylalanine (FMLP) and leukotriene B4 (LTB4) were included for comparison. 2. Local inhibition of protein biosynthesis in the skin using actinomycin-D or cycloheximide blocked 111In-neutrophil accumulation induced by IL-1, but not that induced by the other mediators. 3. Actinomycin-D and cycloheximide had no effect on local plasma protein leakage induced by intradermally-injected C5a des Arg, or that induced by zymosan. 111In-neutrophil accumulation induced by zymosan was, however, partially suppressed. 4. A monoclonal antibody, MoAb 60.3, recognising neutrophil surface CD18 antigen, was preincubated with 111In-neutrophils before intravenous injection. This pretreatment did not affect circulating numbers of radiolabelled cells, but it inhibited their accumulation in response to IL-1, C5a des Arg and the other mediators. 5. The results suggest that neutrophil accumulation induced by IL-1, but not the other mediators, requires local protein biosynthesis, probably in the microvascular endothelium. Neutrophil accumulation to IL-1 and the other mediators appears to require neutrophil surface antigen, CD18. The inflammatory response to zymosan may be mediated by both endogenous C5a des Arg and IL-1.

Animals↗
PubMed1989

Accumulation of 111In-neutrophils in rabbit skin in allergic and non-allergic inflammatory reactions in vivo. Inhibition by neutrophil pretreatment in vitro with a monoclonal antibody recognizing the CD18 antigen.

The mAb 60.3 recognizes the neutrophil CD18 Ag. We have investigated the effect of in vitro pretreatment of radiolabeled neutrophils with mAb 60.3 on their accumulation in vivo. Further, we have compared the in vivo effects of mAb 60.3 with its effects on neutrophil adherence in vitro. Neutrophil accumulation in vivo was measured in response to: 1) exogenous mediators FMLP, C5a des Arg, LTB4 and IL-1; 2) endogenous mediators generated in a non-allergic inflammatory reaction induced by zymosan; and 3) endogenous mediators generated in two allergic inflammatory reactions, a passive cutaneous anaphylactic reaction and a reversed passive Arthus reaction in rabbit skin. Pretreatment of neutrophils with mAb 60.3 inhibited their accumulation in all the responses. The results demonstrate that there is a common mechanism mediating neutrophil accumulation in these inflammatory reactions. Neutrophils pretreated with mAb 60.3 were also unresponsive to chemoattractants in in vitro adherence assays. However, the antibody-treated neutrophils responded normally to FMLP and C5a with respect to granular enzyme release. These results suggest that the basal expression of CD18 Ag is important for the adherence of neutrophils to microvascular endothelial cells stimulated by the local generation, or administration, of chemical mediators in vivo. Despite the fact that mediators such as FMLP can increase CD18 expression in vitro, it appears more likely that such mediators act in vivo by inducing a conformational change in the basally expressed neutrophil adhesive molecules.

Animals↗
PubMed1991

Ethanol impairs certain aspects of neutrophil adhesion in vitro: comparisons with inhibition of expression of the CD18 antigen.

Since ethanol impairs polymorphonuclear leukocyte (PMNL) delivery to inflammatory sites, the effect of ethanol on PMNL adhesiveness was studied in vitro. Ethanol inhibited PMNL aggregation induced by formylmethionylleucylphenylalanine (FMLP) but not by phorbol myristate acetate (PMA), whereas responses to both stimuli were abolished by treating PMNL with monoclonal antibody 60.3 (against the adhesion protein CD18). This antibody also abrogated spontaneous and FMLP-stimulated PMNL adhesion to plastic, whereas ethanol reduced spontaneous but not FMLP-induced adherence. Chemotaxis in Boyden or agarose systems was not diminished by ethanol, but high concentrations of MAb 60.3 inhibited migration under agarose. Nonetheless, upregulation of cell surface expression of CD18 (assessed by immunofluorescence flow cytometry) induced by FMLP or PMA was similarly reduced by ethanol. Thus, ethanol inhibited only certain of PMNL adhesion, and although the stimulated up-regulation of CD18 expression was reduced it is unlikely that ethanol effects were mediated only by this inhibition.

Antigens, CD↗
PubMed2000

Design and synthesis of germline-based hemi-humanized single-chain Fv against the CD18 surface antigen.

The 6.7 murine monoclonal antibody (mAb) recognizes the human CD18 antigen and is therefore of interest as an anti-inflammatory agent. The 6.7 heavy variable chain (VH) was humanized using the closest human germline sequence as the template on to which to graft the murine complementary determining regions (CDRs). Two versions were proposed, one in which the residue proline 45 of the murine form was maintained and another in which this framework residue was changed to the leucine found in the human sequence. These VH humanized versions were expressed in the yeast Pichia pastoris as hemi-humanized single-chain Fv (scFvs), with the VL from the murine antibody. The scFv from the murine antibody was also expressed. The binding activities of the murine and both hemi-humanized scFvs were determined by flow cytometry analysis. All the constructions were able to recognize human lymphocytes harboring CD18, indicating successful humanization with transfer of the original binding capability. Some differences between the two hemi-humanized versions were observed. The method used was simple and straightforward, with no need for refined structural analyses and could be used for the humanization of other antibodies.

Amino Acid Sequence↗
PubMed1994

CD11/CD18 and ICAM-1 expression in a murine foreign body granulomatous lung model.

The expression of leukocyte adhesion molecules (Leu-CAM; CD11/CD18 family) and ICAM-1 was studied on bronchoalveolar lavage (BAL) cells and lung tissue sections from a mouse lung granulomatous model. When foreign body lung granuloma were induced in mice by intratracheal injection of 1.5 x 10(4) Sephadex G-50 beads, total and differential BAL cell counts demonstrated a maximal recovery of macrophages and neutrophils at 3 days. Indirect immunoperoxidase staining patterns indicated that intratracheal challenge with beads activated BAL cells and upregulated expression of CD11b, ICAM-1, and CD18 antigenic markers on macrophages and neutrophils when compared with BAL cells from saline controls. Immunohistochemical staining also confirmed the presence of CD11b on activated macrophages and neutrophils around the beads and of the ICAM-1 antigen in the lung parenchyma of bead challenged mice.

Animals↗
PubMed2002

A feline assay using osteoclasts generated in vitro from peripheral blood for screening anti-resorptive agents.

Musculo-skeletal diseases are a major cause of pain and suffering in cats and several conditions involve increased bone resorption by osteoclasts. However, little is known about the biology of these cells in the cat. In this study we established a method to generate feline osteoclasts from blood mononuclear cells stimulated by macrophage colony stimulating factor (M-CSF) and receptor activator of NF-kappaB ligand (RANKL). Cultured osteoclasts are multinucleated, express tartrate resistant acid phosphatase (TRAP), form F-actin rings and resorb bone. They express alpha(v)beta3 vitronectin receptor and osteoclast enzymes, cathepsin K and MMP9; the myeloid antigen, CD18, and the megakaryocyte/platelet integrin, CD41, are absent. This phenotype is typical of osteoclasts from other species. Three resorption inhibitors were examined for activity against feline osteoclasts. Calcitonin, bisphosphonate and RGD integrin inhibitory peptide all reduced bone resorption at doses similar to those efficacious in rabbit or human. We conclude that blood-derived osteoclast cultures are a suitable in vitro system for assessing the ability of drugs to inhibit bone resorption in domestic cats.

Acid Phosphatase↗
PubMed2000

Ehrlich ascites tumour unbalances splenic cell populations and reduces responsiveness of T cells to Staphylococcus aureus enterotoxin B stimulation.

Tumours must avoid host immune response to survive and proliferate; to achieve this purpose, tumours interact with cells of the immune system by means of tumour secreted factors. The alterations of splenic cell populations in mice bearing the Ehrlich ascites tumour have been studied. A rapid and acute response was observed, characterized by a decrease in both CD4 and CD8 T cells, and a transient increase in the number of B cells, which peaked 2 days after tumour inoculation. An increase in macrophage population and in the homing antigen CD18 was also detected. In vitro incubations of splenic cells with the Staphylococcus aureus enterotoxin B (SEB) showed that tumour induces a state of reduced responsiveness to stimulation of T cells, mainly affecting CD8 T cells, and a diminished IFN-gamma expression.

Animals↗
PubMed1989

Adhesion molecules on the plasma membrane of epidermal cells. I. Human resting Langerhans cells express two members of the adherence-promoting CD11/CD18 family, namely, H-Mac-1 (CD11b/CD18) and gp 150,95 (CD11c/CD18).

The CD11/CD18 family of leukocyte adhesion-promoting proteins is comprised of three members, each composed of a shared beta subunit (CD18) noncovalently associated with unique alpha subunits (CD11a, CD11b and CD11c respectively). Such three heterodimers, named LFA-1 (CD11a/CD18), H-Mac-1 (CD11b/CD18) and gp150,95 (CD11c/CD18), are involved in mediating leukocyte adhesion in virtually all phases of the immune responses. Since Langerhans cells are regarded as cutaneous leukocytes, we investigated the expression of the members of the CD11/CD18 family on Langerhans cells. A vast series of immunostaining procedures was carried out, using monoclonal antibodies anti-CD11a, -CD11b, -CD11c, and -CD18. Normal skin frozen sections and epidermal sheets were investigated by immunohistology and immunofluorescence; suspended freshly isolated epidermal cells were processed using immunogold techniques, performed in both transmission and scanning electron microscopy, including double labeling procedures and semiquantitative analysis of the labeled cells. The results demonstrated the expression on the membrane of Langerhans cells of the CD11b, CD11c and CD18 antigens, thus indicating that at least both the H-Mac-1 (CD11b/CD18) and the gp150,95 (CD11c/CD18) members of the CD11/CD18 family are detectable on the cell surface of human resting Langerhans cells. Since both such moieties serve as adhesion molecules in (a) cell-cell interactions and in (b) leukocyte migration and localization, the present results suggest that H-Mac-1 and gp150,95 might display a key role (a) in promoting interactions between Langerhans cells and other cells, and (b) in guiding the migration and localization of Langerhans cells.

Adolescent↗
PubMed1993

Inhibition of leukocyte adhesion to endothelial cells of human umbilical vein by Y-24180, an antagonist of platelet-activating factor.

Effect of Y-24180 (4-(2-chlorophenyl)-2-[2-(4-isobutylphenyl)ethyl]-6,9-dimethyl-6H- thieno [3,2-f][1, 2, 4]triazolo[4,3-a][1,4]diazepine), an antagonist of platelet-activating factor (PAF), on adhesion of leukocytes to endothelial cells of human umbilical vein was examined. Y-24180 inhibited the adhesion of guinea-pig peritoneal exudate cells activated by leukotriene B4 to endothelial cells in a concentration-dependent manner. WEB2086, another PAF antagonist, did not show the inhibitory effect. Inhibition by Y-24180 was not influenced by addition of PAF. Y-24180 had no effect on the expression of intercellular adhesion molecule-1 or endothelial-leukocyte adhesion molecule-1 on endothelial cells activated with interleukin-1 beta, while it suppressed the expression of CD18 antigen on human peripheral blood polymorphonuclear cells activated with leukotrien B4, inhibiting their adhesion to endothelial cells activated with interleukin-1 beta. In oxazolone-induced ear edema in mice, which involves delayed-type hypersensitivity with infiltration by inflammatory cells, Y-24180 dose-dependently inhibited the increase in ear weights, but WEB2086 did not. These results indicate that Y-24180 inhibits not only the actions of PAF but also the adhesion of leukocytes by suppressing the expression of CD18 antigen, inducing the inhibition of infiltration by inflammatory cells.

Animals↗
PubMed1998

Dominant-negative effect of the lymphocyte function-associated antigen-1 beta (CD18) cytoplasmic domain on leukocyte adhesion to ICAM-1 and fibronectin.

The cytoplasmic domains of LFA-1 (CD11a/CD18) are thought to play an important role in the regulation of LFA-1 function. To further elucidate the role of the LFA-1 cytoplasmic domains, we transfected chimeric proteins consisting of the extracellular domain of CD4 fused with the transmembrane and cytoplasmic domains of LFA-1 into T and B cell lines, EL-4 and A20, respectively, and examined their effects on LFA-1-mediated cell adhesion. The CD4/18, but not CD4/11a, chimera profoundly inhibited LFA-1-mediated cell adhesion to ICAM-1, as well as cell spreading following cell adhesion. Unexpectedly, cell adhesion to fibronectin was also inhibited by the CD4/18 chimera. The CD4/18 chimera did not affect the expression of endogenous LFA-1 or the association of CD11a and CD18. Truncation of the carboxyl-terminal 13 amino acid residues of the CD18 cytoplasmic domain of the chimera completely abrogated the inhibitory effect on LFA-1. Among these amino acid residues, the carboxyl-terminal six residues were dispensable for the inhibitory effect in EL-4 cells, whereas it significantly reduced the inhibitory activity of CD4/18 in A20 cells. A larger truncation of the CD18 cytoplasmic domain was needed to fully abrogate the inhibitory effects of CD4/18 on the adhesion to fibronectin. These results show that 1) the CD4/18 chimera has dominant-negative effects on cell adhesion mediated by LFA-1 as well as fibronectin receptors, and 2) amino acid residues of the CD18 cytoplasmic domain involved in the inhibition of LFA-1 seem to be different from those for fibronectin receptors.

Amino Acid Sequence↗
PubMed1996

Role of endothelin in the pathophysiology of renal ischemia-reperfusion in normal rabbits.

The present study addressed the acute effects of endothelin-1 on renal function and neutrophils accumulation in the setting of in vivo severe (60 min) acute ischemia/reperfusion. Ischemia/reperfusion decreased renal functional parameters and increased renal neutrophil accumulation and medullary congestion. All these parameters markedly improved with the intrarenal administration of anti-endothelin-1 antiserum. Comparatively, the intrarenal infusion of endothelin-1 decreased renal function and increased neutrophil accumulation. Abnormalities in renal histology were, however, less pronounced than with ischemia/ reperfusion. In experiments using rabbit isolated perfused kidneys, endothelin-1 induced the accumulation of labeled neutrophils. This accumulation was similar to that observed in kidneys obtained after 60 minutes of ischemia plus 60 minutes of reperfusion. Both endothelin and ischemia/ reperfusion effects were counteracted by an anti-endothelin antibody. In further in vitro studies, we found that endothelin-1-induced the expression of the CD18 antigens on the neutrophil surface. In subsequent experiments based on this effect of ET-1 on CD18 antigens, a blockade of both ischemia/reperfusion-induced and endothelin-1-induced neutrophil accumulation was obtained by infusion an anti-CD18 antibody. In conclusion, our experiments disclosed the critical role of endothelin-1 as a major promoter of early neutrophil accumulation after ischemia/reperfusion, which occurred through an integrin-mediated mechanism.

Animals↗
PubMed1988

Purification in large scale and characterization of the human leukocyte adhesion glycoprotein GP90 (CD18).

The leukocyte adhesion 90-kDa glycoprotein GP90 (antigen CD18) is non-covalently associated separately with cell-surface glycoproteins GP160 (antigens CD11a, TA-1, LFA-1), GP155 (antigens CD11b, OKM1, MO1) or GP130 (antigens CD 11c, Leu-M5). Large amounts of these protein complexes were purified to homogeneity from blood mononuclear leukocytes by immunoaffinity chromatography using a monoclonal antibody. GP90 was further isolated by preparative gel electrophoresis in the presence of sodium dodecyl sulfate. Rabbit antiserum towards the complex inhibited phorbol-ester-induced adhesion of leukocytes. The antiserum towards purified GP90 reacted more strongly with the denatured GP90 protein, but showed reactivity also with GP160 protein, indicating structural homologies between GP90 and GP160. The amino acid composition of GP90 was determined. Its N-terminus was found to be blocked. Treatment of GP90 with endo-beta-N-acetylglucosaminidase F, but not with endo-beta-N-acetylglucosaminidase H, reduced the apparent molecular mass to 75 kDa, indicating the presence of five or six N-linked complex-type oligosaccharides/molecule.

Amino Acids↗
PubMed1990

Protein kinase C-mediated regulation of the expression of CD14 and CD11/CD18 in U937 cells.

We used the U937 cell line to analyze CD14, CD11/CD18, HLA class-I and DR antigen expression during PMA-induced differentiation. Treatment of U937 cells with PMA markedly increased CD14, CD11a, CD11b and CD18 antigen expression, and slightly increased CD11c expression. Protein kinase C may play a major role in regulating the expression of these antigens. The protein kinase inhibitor H7 abrogated the inductive effect of PMA. Calcium ionophore, when added alone or in the presence of PMA, had no effect. The inhibitory effect of the calcium antagonist verapamil, EGTA, and of chlorpromazine, an antagonist of calcium-binding proteins, supports a role for calcium-dependent protein kinase C in the up-regulation of CD14 and CD11/CD18 surface expression. The specific calmodulin inhibitors R24571 and W7 had no effect on antigen expression. Our findings suggest that protein kinase C activation is an important step in the PMA-induced differentiation of U937 cells.

Antigens, CD↗
PubMed1991

Induction of LFA-1-mediated homotypic adhesions in promonocytic U-937 cells occurs independently of cell differentiation.

The differentiation of monocytes into macrophages occurs along with a marked increase in LFA-1-dependent intercellular adhesions. Similarly, the phorbol ester-induced differentiation of U-937 promonocytic cells into macrophage-like cells is morphologically characterized by an important increase in LFA-1/ICAM-1-dependent intercellular homotypic adhesions. Since an important functional role in activation of human T cells has been demonstrated for LFA-1-dependent adherence, we have analyzed whether the induction of LFA-1-dependent intercellular adhesion of human monocytic cells is necessarily accompanied by differentiation of these cells. We found that treatment of the promonocytic U-937 cells with the anti-LFA-1 mAb NKI-L16 induces formation of intercellular clusters, but does not induce cell differentiation as determined by several differentiation markers. These markers include the arrest of cell proliferation, production of reactive oxygen species, changes in the cell surface expression of differentiation-associated antigens such as the transferrin receptor, CD11b and CD11c and changes in the levels of several specific gene transcripts such as CD18 antigen, c-myc, ornithine decarboxylase and vimentin. These findings suggest that LFA-1-dependent adhesion and differentiation of monocytic cells are independent processes.

Antibodies, Monoclonal↗
PubMed1991

Multiple receptors for endotoxin.

Recent studies have identified three classes of receptor molecules involved in recognition of endotoxin. Two classes of receptors, the CD18 antigens and the scavenger receptor, recognize lipopolysaccharide directly and function principally in its catabolism. A third molecule, CD14, recognizes lipopolysaccharide with the aid of a serum protein, lipopolysaccharide-binding protein, and may be a principal mediator of secretory responses of leukocytes.

Animals↗
PubMed1994

Cross-linking of CD18 in human neutrophils induces an increase of intracellular free Ca2+, exocytosis of azurophilic granules, quantitative up-regulation of CD18, shedding of L-selectin, and actin polymerization.

Polymorphonuclear leukocytes (PMNs) exert most of their physiological functions while adherent to surfaces rather than in suspension. PMN adhesion is largely dependent on the function of the beta 2 integrins, CD11a,b,c/CD18. We mimicked engagement of beta 2 integrins by antibody cross-linking of CD18 on isolated human PMNs using both intact monoclonal antibody and F(ab')2 fragments. Within seconds of CD18 cross-linking, we observed a significant, transient rise of intracellular free Ca2+ concentration by 200-300 nM, which was largely due to Ca2+ mobilization from intracellular stores. The Ca2+ signal was blocked after pretreatment with phorbol myristate acetate, an activator of protein kinase C, but not with herbimycin A, a potent inhibitor of tyrosine kinases. In addition to the rise of intracellular free Ca2+ concentration, CD18 cross-linking induced exocytosis of azurophilic granules (release of 26% of total PMN elastase), which was significantly inhibited by herbimycin A. Moreover, 2.2-fold up-regulation of CD18 antigen and significant down-regulation of surface expression of the granulocyte adhesion molecule L-selectin were induced. Granulocyte F-actin content as measured by nitrobenzoxadiazole-phallacidin increased significantly 1 min after CD18 cross-linking. By contrast, CD18 cross-linking by soluble antibodies did not induce superoxide production, but PMNs bound to immobilized monoclonal antibodies against CD18 released significant amounts of superoxide. Initial signaling through beta 2 integrins does not appear to be mediated by a phospholipase C isoform activated through tyrosine phosphorylation, because the Ca2+ signal was not altered by herbimycin A. However, more complex cellular responses including exocytosis were found to require tyrosine phosphorylation. We show that engagement of beta 2 integrins provides an important stimulatory signal to PMNs inducing degranulation, modulation of L-selectin, and cytoskeletal changes.

Actins↗
PubMed1996

An antibody to CD44 enhances hematopoiesis in long-term marrow cultures.

Monoclonal antibody S5, which is specific for CD44, facilitates engraftment of major histocompatibility complex (MHC)-mismatched canine bone marrow (BM) when infused into recipient animals before total body irradiation (TBI) and marrow infusion. The precise mechanism by which S5 facilitates engraftment is not known. Previously published data in a murine long-term bone marrow culture (LTBMC) model with other anti-CD44 monoclonal antibodies (mAbs) demonstrated an abrogation of myelo- and lymphopoiesis in LTBMC. To address this issue in an in vitro setting, the effect of S5 on canine myelopoiesis in LTBMC was investigated. The data indicate that treatment of LTBMC with S5 causes an absolute increase in the number of progenitor cells as measured by a colony-forming unit-granulocyte/macrophage (CFU-GM) assay compared to cultures treated with control mAb (p < 0.0001). This effect was not observed with three other anti-CD44 mAbs used (Hermes-1, S3, and IM7). In addition, a concomitant decrease in the production of nonadherent cells was noted (p < 0.0001). These effects were evident in both autologous and allogeneic LTBMC systems. mAb S5 has been shown to enhance natural killer (NK) activity, and more recent data indicate the increased cytoxic effect to be partially mediated through CD18. Thus, a possible role for modulation of the CD18 antigen in LTBMC by S5 was assessed by addition of the anti-CD18 mAb 60.3. While the S5-induced reduction in total nonadherent cell production was not changed by addition of 60.3, the increase in progenitor cells stimulated by S5 was abrogated. These findings suggest a role for anti-CD44 antibody in changes in the marrow microenvironment that may be responsible for facilitation of donor engraftment and, at least in part, CD18 may be involved in this phenomenon. The establishment of this in vitro LTBMC model will enable the mechanism to be further dissected.

Animals↗
PubMed1993

Human immunodeficiency virus-associated oral Kaposi's sarcoma. A heterogeneous cell population dominated by spindle-shaped endothelial cells.

Cell lineage and cell function antigens were studied immunohistochemically in human immunodeficiency virus-associated oral Kaposi's sarcoma to provide insight into tumor pathogenesis. All tumors were composed predominantly of spindle cells that expressed endothelium-associated antigens, CD34 and CD36 (factor VIII-related antigen was expressed by considerably fewer numbers of tumor cells). Infrequently, spindle tumor cells also expressed actin. Factor XIIIa positive spindle and dendritic stromal cells comprised up to 9% of the tumor cell population. Other spindle and dendritic cells expressing macrophage-associated antigen, CD68, accounted for up to 15% of the tumor cells. Mast cells occurred frequently within and around tumors. Leukocyte function antigen (CD18) was expressed by approximately 13% of tumor cells, and its ligand, intercellular adhesion molecule (ICAM), was expressed by some tumor-associated capillaries (which also expressed endothelial leukocyte adhesion molecule, ELAM) and occasional stromal cells. Staining for proliferating cell nuclear antigen was noted in both interstitial and vascular lining cells. All tumors were non-reactive for human Papillomavirus antigen and HIV p24 antigen. Oral KS is a heterogeneous cellular proliferation composed predominantly of endothelial or endothelium-related spindle cells. Other spindle/dendritic (XIIIa-positive and CD68-positive) cells and mast cells are also present and may contribute to tumor development. ICAM and ELAM expression within tumors may assist infiltration of macrophages and other inflammatory cells into these lesions.

AIDS-Related Opportunistic Infections↗