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PubMed1997

PU.1 negatively regulates the CD11c integrin gene promoter through recognition of the major transcriptional start site.

CD11c integrin expression is restricted to myeloid cells and activated B lymphocytes, mainly through the collaborative action of Sp1 and members of the AP-1 and C/EBP transcription factor families on the proximal region of the CD11c gene promoter. While analyzing the role of an initiator-like sequence at the major transcriptional start site, an inverted consensus GGAA Ets binding site was identified as a negative regulatory element whose disruption increases the activity of the CD11c promoter. The GGAA element was specifically recognized by PU.1 in THP-1 monocytic cells and by PU.1 and GABP-related proteins in U937 promonocytic cells. Mutational analysis indicated that PU.1 recognition depends not only on the GGAA consensus element but also on flanking sequences. The functional relevance of PU.1 binding was assayed in transactivation experiments in HeLa cells, where PU.1 co-expression led to a significant decrease in the activity of the CD11c promoter, demonstrating that PU.1 inhibits the activity of the CD11c promoter through a PU.1 binding site located at the major transcriptional start site (PU1-5). The inhibitory action of PU.1 on CD11c is in contrast with its positive regulatory effect on the CD11b and CD18 integrin gene promoters, which might contribute to the differentially regulated expression of CD11b/CD18 and CD11c/CD18 during monocyte extravasation and terminal maturation. In addition, since PU.1 transcriptional activity correlates with macrophage proliferation, PU.1 might modulate CD11c gene transcription according to the proliferative state of the cell.

Base Sequence↗
PubMed2005

Interaction of ICAM-1 with beta 2-integrin CD11c/CD18: characterization of a peptide ligand that mimics a putative binding site on domain D4 of ICAM-1.

The integrin CD11c/CD18 plays a role in leukocyte and cell matrix adhesion and is highly expressed in certain hematopoietic malignancies. To better characterize ligand binding properties, we panned random peptide phage-display libraries over purified CD11c/CD18. We identified a phage expressing the circular peptide C-GRWSGWPADL-C. C-GRWSGWPADL-C phage bound specifically to CD11c/CD18 expressing monocytes but not CD11c/CD18 negative lymphocytes and showed 5 x 10(3)-fold higher binding to purified CD11c/CD18 than control phage, without binding to CD11b/CD18. Peptide sequence analysis revealed a similar sequence in domain D5 of ICAM-1 and an alternative, phase-shifted motif in domain D4. Surface plasmon resonance experiments demonstrated direct interaction of ICAM-1 and CD11c/CD18. A soluble fusion protein containing the extracellular domain of ICAM-1 abolished C-GRWSGWPADL-C phage binding to CD11c/CD18. Moreover, synthetic monomeric circular peptide C-GRWSGWPADL-C bound specifically to CD11c/CD18 and inhibited ICAM-1 binding. Its rather low binding affinity and inability to displace pentavalent C-GRWSGWPADL-C phage from CD11c/CD18 suggests that a multimeric display of the selected peptide is essential for high affinity binding. Using ICAM-1 deletion constructs, we showed that domain D4 is required for interaction with CD11c/CD18, suggesting that C-GRWSGWPADL-C phage binds specifically to CD11c/CD18 by structurally mimicking the interaction site on D4 of ICAM-1.

Binding Sites↗
PubMedDate not supplied

Immunophenotype of blast cells in acute myeloid leukemia may be a useful predictive factor for outcome.

The immunophenotype of peripheral blood blast cells was tested in 92 patients with acute myeloid leukemia (AML), who were diagnosed and treated at single centre, St Bartholomew's Hospital, from 1978-1987 with a standard adriamycin, cytosine arabinoside and 6-thioguanine regimen. Immunological analysis involved standard fluorescence flow cytometry and utilized 31 monoclonal antibodies to known myeloid antigens (of CD groups 11b, 11c, 13, 14, 15, 16, w17, 31, w32, 33, 34, 35 and 36), a number of relatively less well studied antibodies with potential specificity for AML, and a series of control antibodies to T and B lymphocytes, platelets, erythrocytes and of widespread distribution (CD45, leucocyte common; HLA-DR). The results highlighted a number of antibodies with wide myeloid reactivity, in addition to CD13 and 33 (present in 66 per cent and 76 per cent of cases, respectively), which may be of immunodiagnostic use. A number of correlations between AML cell immunophenotype and FAB morphology subtype were found; in particular five antibodies (CD11c, 10.1, Tu3, CD15 and CD16), of both predominant granulocytic and monocytic reactivity, reacted with cells of AML-M5 subtype (p less than 0.05). There was no significant correlation between immunophenotype and clinical and pathological features at presentation. Correlation with clinical outcome was not a prominent feature, in contrast to some reports based on multicentre data. However, of particular note was the strong association between early death (at less than 2 months) and the coexpression of Leucocyte Function Associated (LFA) antigens, CD11b and 11c, on patient's blast cells (p = 0.003). The relationship was independent of clinical features and persisted even if AML-M5 cases were excluded. The significance of this latter finding is unclear, but may be related to the known role of CD11b and 11c LFA antigens in the cellular response to infection.

Adult↗
PubMed1985

The origin of the very variable haemolytic activities of the common human complement component C4 allotypes including C4-A6.

The human complement component C4 occurs in many different forms which show big differences in their haemolytic activities. This phenomenon seems likely to be of considerable importance both physiologically and pathologically. C4 is coded by duplicated genes between HLA-D and HLA-B loci in the major histocompatibility complex in man. Several fold differences in haemolytic activity between products of the two loci C4-A and C4-B have been correlated with changes of six amino acid residues in this large protein of 1722 residues and with differences of several fold in the covalent binding of C4 to antibody-antigen aggregates. Some allotypes of one locus also differ markedly, notably C4-A6 which has 1/10th the haemolytic activity of other C4-A allotypes. A monoclonal antibody affinity column has been prepared which is able to separate C4-A from C4-B proteins and, using serum from an individual expressing only the C4-A6 allele at the C4-A locus, C4-A6 protein has been prepared. Investigation has shown C4-A6 to have the same reactivity as other C4-A allotypes except in the formation of the complex protease, C5 convertase. This protease is formed from C4, C2 and C3 and if C4-A6 is used it has approximately 1/5th the catalytic activity compared with other C4-A allotype. Allelic differences in sequence identified in C4 proteins so far are few and it is probable that the big difference in catalytic activity of C5 convertase is caused by very small changes in structure.

Alleles↗
PubMed1988

Relative contribution of the leukocyte molecules Mo1, LFA-1, and p150,95 (LeuM5) in adhesion of granulocytes and monocytes to vascular endothelium is tissue- and stimulus-specific.

Adhesion of human monocytes and granulocytes to vascular endothelium plays an important role in migration of these cells to inflammatory sites in tissues. A family of three human leukocyte heterodimeric surface molecules named Mo1, LFA-1, and p150,95 (LeuM5) has been shown to mediate leukocyte adhesion to confluent monolayers of human umbilical vein endothelial cells (HUVE). The relative contribution of each of the three molecules in leukocyte endothelial adhesion was studied using a variety of stimuli. Purified human granulocytes and monocytes were radiolabelled and incubated with HUVE for 45 minutes in a 37 degrees C humidified 5% CO2 incubator in the presence or absence of subunit-specific monoclonal antibodies (MAbs). Adhesion was assessed by quantitation of endothelial cell-associated radioactivity and confirmed by microscopic evaluation. MAbs directed against the alpha subunit of LFA-1 as well as to the beta subunit common to all three antigens significantly inhibited unstimulated monocyte adhesion to HUVE. Small but significant inhibiton was also observed using MAbs directed against Mo1a and p150. Phorbol myristate acetate (PMA)-induced grranulocyte adhesion to HUVE was significantly inhibited by anti-Mo1a and anti-beta, but not by anti-LFA-1a or anti-p150. When HUVE were prestimulated by recombinant IL-1, a different pattern of antigen utilization by granulocytes was observed. MAbs directed against each of the three alpha subunits as well as the common beta subunit all inhibited granulocyte adhesion to HUVE. Furthermore the effect of the three anti-alpha subunit MAbs on granulocyte-HUVE adhesion was additive. These studies show that relative contribution of Mo1, LFA-1, and p150,95 to leukocyte endothelial adhesion varies depending on the cell type and the stimulus used. These studies also reveal a novel role for p150,95 in promoting monocyte and granulocyte adhesion to HUVE.

Antibodies, Monoclonal↗
PubMed1989

Heterogeneity of macrophages in the rat evidenced by variability in determinants: two new anti-rat macrophage antibodies against a heterodimer of 160 and 95 kd (CD11/CD18).

A set of three monoclonal antibodies (MoAbs), ED1, ED2, and ED3, has been shown to recognize in situ different subsets of macrophages in the rat. This macrophage diversity can be correlated with differences in stage of differentiation of cells belonging to one lineage. The present study quantifies this antigen distribution in the macrophage fractions of several lymphoid organs provided by Percoll centrifugation. Four new MoAbs (ED4, ED7, ED8, and ED9) raised against macrophages are included in this study. The tissue distribution of each of the four new MoAbs is determined by immuno- and enzyme-histochemistry on cryostat sections. The MoAbs recognize distinct subpopulations of macrophages. The new MoAbs ED4, ED7, ED8, and ED9 recognize granulocytes and other unrelated cell types, as well as cells of the mononuclear phagocyte system. ED7 and ED8 recognize a surface heterodimer of Mr 160,000 and 95,000.

Animals↗
PubMed2005

Human cytomegalovirus downregulates complement receptors (CR3, CR4) and decreases phagocytosis by macrophages.

Human cytomegalovirus (HCMV) infection is associated with an increased susceptibility to opportunistic infections. Although the subversion of adaptive immune responses has been extensively studied, the consequences of HCMV infection on natural immune responses are not well documented. A striking selective downmodulation of CD11b/CD18 (CR3) or CD11c/CD18 (CR4) was found upon HCMV infection, on two models, the monocytic THP-1 cell line and monocyte- derived macrophages. HCMV-infected macrophages have an altered adhesion/phagocytic capacity to Candida albicans, a pathogen responsible for some opportunistic infections in immunocompromised patients. These results suggest a new mechanism implicated in the augmentation of opportunistic infections in HCMV patients.

Candida albicans↗
PubMed1996

Structure-based modeling of the ligand binding domain of the human cell surface receptor CD23 and comparison of two independently derived molecular models.

CD23, a type II membrane receptor protein, recognizes four different ligands via its extracellular C-type lectin domain: immunoglobulin E (IgE), CD21, and the beta 2-integrins CD11b and CD11c. CD23 specifically interacts in a calcium-dependent manner, "lectin-like" with carbohydrate moieties expressed on CD21 and CD11b/c, but also "lectin-unlike" with protein epitopes on IgE. As a first step in analyzing the multiple binding specificities associated with CD23 in more detail, we report a detailed molecular model of the lectin-like domain of human CD23 (hCD23). The model was built based on information provided by X-ray structures of mannose binding protein (MBP) and E-selectin, both of which are members of the calcium-dependent (C-type) lectin superfamily. Sequence-structure comparisons suggest that hCD23 is structurally more similar to MBP than to E-selectin. The hCD23 model is compared to an independently derived model. Although the CD23-carbohydrate and CD23-protein interactions are both calcium dependent, analysis of the model suggests the presence of distinct binding sites for these ligands.

Amino Acid Sequence↗
PubMed1996

Inhibitory effects of negatively charged liposomes on nitric oxide production from macrophages stimulated by LPS.

The effects of liposomes on nitric oxide (NO) productions induced by lipopolysaccharide were investigated using thioglycollate-induced mouse peritoneal macrophages. Negatively charged liposomes composed of phosphatidic acid (PA-liposomes) and phosphatidylserine (PS-liposomes) showed inhibitory effect on NO production in a dose dependent manner, but not in liposomes composed of phosphatidylcholine (PC-liposomes). Pretreatment of macrophages with liposomes was required in order to observe the inhibitory effect on NO production. NO production induced by IFN-gamma was also inhibited by negatively charged liposomes. To clarify the mechanism of inhibitory effect of liposomes, immune blotting was performed using anti mouse inducible nitric oxide synthase (iNOS) antibody. An immunoreactive band at 130 kDa was observed in the extract of control and PC-liposome- treated macrophages, whereas a faint or no band was observed in PS- and PA-liposome-treated ones. These finding revealed that the inhibition of NO production by negatively charged liposomes could be a result in the inhibition of iNOS induction, but not enzyme activity.

Animals↗
PubMed1996

Modulation of ICAM-1 levels on U-937 cells and mouse macrophages by interleukin-1 beta and dexamethasone.

Differentiation of U-937 cells with phorbol ester (10 nM) induced a time-dependent (24 h or 48 h) increase of adhesion molecules and lipocortin 1 expression on the cell surface. Stimulation with interleukin-1 beta for a further 16 h increased the levels of intercellular adhesion molecule-1, and this effect was inhibited by co-incubation with 0.1-1 microM dexamethasone. The effect of the glucocorticoid was not modified by addition of a specific anti-lipocortin 1 monoclonal antibody (mAb 1A, 5 micrograms/ml). This opposite modulatory role of interleukin-1 and dexamethasone on intercellular adhesion molecule-1 expression was also, for the first time, observed in vivo using mouse peritoneal macrophages: a four-fold increase in intercellular adhesion molecule-1 expression was measured after local administration of the cytokine (5 micrograms/kg) and this effect was greatly inhibited (> 70%) by co-injection with 1 microgram dexamethasone. In conclusion, modulation of intercellular adhesion molecule-1 expression by glucocorticoids is an effect independent endogenous lipocortin 1, and it is an in vivo feature of these potent anti-inflammatory drugs.

Animals↗
PubMed1996

Effects of 1,25-dihydroxy vitamin D3 on all-trans retinoic acid sensitive and resistant acute promyelocytic leukemia cells.

Following challenge of the acute promyelocytic leukemia (APL) cell line, NB4, with 1, 25 dihydroxy vitamin D3 (1, 25 D3), no increase in the expression of the monocytic surface markers, CD11c, CD14 and HLA-DR is observed. By contrast, 1, 25 D3 increases the expression of CD11b, an early myeloid marker and enhances adherence to plastic following priming of the cells with phorbol 12-myristate 13-acetate (PMA). NB4.306 and NB4.007/6, two all-trans retinoic acid-resistant cell lines originated from NB4 promyelocytes and lacking expression of a complete form of PML-RAR, are totally resistant to 1, 25 D3-dependent induction of CD11b. In addition, NB4.306 cells do not show enhanced plastic adherence following treatment with the vitamin D metabolite and PMA. NB4 and NB4.306 express similar amounts of the transcripts coding for the vitamin D3 receptor and the retinoid accessory receptors, RXR alpha and RXR beta, both in basal conditions and upon treatment with 1, 25 D3.

Antigens, CD↗
PubMed1999

Characteristics of fibrinogen binding to the domain of CD11c, an alpha subunit of p150,95.

beta2 integrins on leukocytes play important roles on cell-cell or cell-matrix adhesion through their ability to bind multiple ligands. The alpha subunits of leukocyte CD11/CD18 integrins contain an approximately 200-amino-acid inserted domain (I-domain) which is implicated in ligand binding function. To understand the characteristics of ligand binding to the alpha subunit of beta2 integrin p150,95 (CD11c/CD18), a recombinant form of the I-domain of CD11c was generated and analyzed for the interaction with fibrinogen, one of the ligands of p150,95. It was found that the CD11c I-domain bound fibrinogen specifically. Fibrinogen binding to the CD11c I-domain was inhibited by a molar excess of fragment E, a central domain of fibrinogen, and not by that of fragment D, a distal domain of fibrinogen, suggesting that CD11c/CD18 recognizes a central domain of fibrinogen. Divalent cations such as Mg(2+) and Mn(2+) were required for fibrinogen binding to the CD11c I-domain. Also alanine substitutions on the putative metal binding sites of the CD11c I-domain such as Asp(242) and Tyr(209) reduced its ability to bind fibrinogen. These data reinforce the fact that the divalent cation is a prerequisite for ligand binding of the CD11c I-domain.

Amino Acid Substitution↗
PubMed2000

Potent inhibition of dendritic cell differentiation and maturation by vitamin D analogs.

We show that the immunosuppressive effects of 1alpha, 25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) are due, in part, to inhibition of the T cell stimulatory functions of dendritic cells (DCs). Addition of 10(-12) and 10(-8) M 1alpha,25(OH)(2)D(3) to murine DC cultures resulted in a concentration-dependent reduction in levels of class II MHC and the co-stimulatory ligands B7-1, B7-2, and CD40 without affecting the number of DCs generated. Higher concentrations of 1alpha,25(OH)(2)D(3) reduced DC yield. The capacity of DCs to induce proliferation of purified allogeneic T cells was reduced by 1alpha,25(OH)(2)D(3). The vitamin D(3) analog, 1alpha,25(OH)(2)-16-ene-23-yne-26,27-hexafluoro-19-nor -D(3), exerted identical effects at 100-fold lower concentrations. Inhibition of DC maturation and stimulatory function was absent in cultures from mice genetically lacking vitamin D receptors (VDR). Vitamin D analogs effectively reduce DC function via VDR-dependent pathways.

Animals↗
PubMed2002

Loops within the CD11c I domain critical for specific recognition of fibrinogen.

The I domains of CD11 are responsible for the binding of ligands and have a unique structure with 6-7 alpha helices and 6 beta sheets with interconnecting loops. To determine loops recognizing fibrinogen in CD11c I domain, five oligopeptides corresponding to CD11c loops were used to prevent fibrinogen binding to isolated CD11c I domain. The results of the inhibition experiment indicated that all of the loops except the one between E-beta sheet and 6-alpha helix were involved in the binding to fibrinogen. The peptide beta D alpha 5 and alpha 3 alpha 4 showed higher inhibitory activity than others, and the combination of four peptides blocked fibrinogen binding to the I domain completely. These peptides (beta A alpha 1, alpha 3 alpha 4, beta D alpha 5 and beta F alpha 7) could block THP-1 cell binding to fibrinogen coated surface as well. Alanine substitution of amino acids on the I domain such as Y249A and Q201A (which are on the loops beta D-alpha 5 and alpha 3-alpha 4 respectively) abolished fibrinogen binding, while mutation on the loop beta E-alpha 6 (Q273A) had no effect on fibrinogen binding. Taken together, the results from this study suggest that the loops on the top of CD11c I domain such as loop beta A-alpha 1, alpha 3-alpha 4, beta D-alpha 5 and beta F-alpha 7 are involved in fibrinogen binding, and two loops (alpha 3-alpha 4 and beta D-alpha 5) are more important than others for the recognition of fibrinogen.

Amino Acid Sequence↗
PubMed1999

Expression of adhesion molecules in chronic serum sickness in rats.

Peripheral blood leukocytes infiltrate the kidney in chronic serum sickness (CSS). We therefore studied the expression of CD54 and its ligands CD18 and CD11b/c in CSS in 10 rats with CSS, 6 rats immunized similarly who did not developed proteinuria (no-CSS group), and 10 normal rats (control group). Intense (6 to 35 times more than controls) leukocyte infiltration was observed in CSS. The CSS group over-expressed CD54 in glomeruli and interstitium in association with increments in CD18- and CD11b/c-positive cells ranging 2.5 to 7 times the number found in controls. 75% of infiltrating leukocytes expressed CD18 and 87% expressed CD11b/c. The non-CSS group had leukocyte infiltration and expression of adhesion molecules similar to control group. Adherence of CD43-positive cells to renal tissues was 4 times higher in renal tissue from CSS rats than to normal kidney. Pretreatment with corresponding Mabs reduced adherence by half. We concluded that over-expression of CD54 and its ligands CD18 and CD11b/c in infiltrating leukocytes occur in CSS. Binding experiments suggest the functional relevance of these molecules.

Animals↗
PubMed2002

Immunogenicity and therapeutic efficacy of dendritic-tumor hybrid cells generated by electrofusion.

Dendritic cells (DCs) are potent antigen-presenting cells capable of inducing strong immune responses to weak tumor-associated antigens. Among various DC-based approaches, cancer immunotherapy with DC-tumor fusion hybrids offers advantages of polyclonal stimulation of a diverse array of tumor antigens. However, prevalent fusion methods using chemical fusogens such as polyethylene glycol often result in toxicity and low fusion efficiency. In this article, we describe an electrofusion technique, applicable to processing large numbers of cells with consistent and high fusion efficiency. Generation of fusion hybrids was verified by unequivocal experimental evidence. In animal models, fusion hybrids expressed the mature DC-like phenotype. They stimulated both CD4 and CD8 tumor-specific T cells to secrete interferon-gamma in vitro. In immunotherapy, a single vaccination with DC-tumor fusion cells along with interleukin-12 as an adjuvant eradicated tumors established in the skin nd lung. These results provide an impetus for treating cancer patients with similarly generated cells.

Animals↗
PubMed1996

The biologic role of B2 integrins in the host response to expanded polytetrafluoroethylene.

We hypothesized that the adherence of leukocytes to a vascular graft surface is mediated by B2 integrins. We studied integrin expression and monoclonal antibody inhibition of peripheral blood leukocyte (PBL) binding in vitro and CD11b expression in vivo. Human PBL were grown on ePTFE in culture and labeled with monoclonal antibodies to CD11a, -b, -c, and/or CD18. Percentage of monoclonal antibody binding and inhibition of leukocyte adherence was studied for up to 30 min using flow cytometry. ePTFE segments were implanted subcutaneously in SH-1 mice and PBL harvested 4 days later. PBL binding of monoclonal antibodies against CD11b was measured using flow cytometry. CD18 was constitutively expressed and CD11a decreased over time. CD11b increased from 41 to 62% and CD11c increased transiently (P < 0.003, P < 0.005). Inhibiton of PBL adherence was greatest by CD11b (34%) and CD11b + CD18 (57%) (P < 0.005, P < 0.0025). Implanted ePTFE caused a fourfold increase in PBL monoclonal antibody binding of CD11b (P < 0.001) compared to sham, Staphylococcus aureus alone, and combination of ePTFE and S. aureus. In conclusion, leukocyte integrins play a central role in the interaction between PBLs and ePTFE as measured by binding of monoclonal antibodies and inhibition of PBL adherence. This is also true in vivo since PBL increase CD11b expression four times when ePTFE is compared to sham. These observations indicate a potential role in vivo for B2 integrins in vascular prosthetic infections.

Animals↗