A discrete subpopulation of human monocytes expresses a neutrophil-like proinflammatory (P) phenotype

1994 ◽  
Vol 267 (6) ◽  
pp. L775-L785 ◽  
Author(s):  
C. A. Owen ◽  
M. A. Campbell ◽  
S. S. Boukedes ◽  
R. A. Stockley ◽  
E. J. Campbell
Keyword(s):  
Cell Surface ◽  
Proteinase Inhibitors ◽  
Solid Phase ◽  
Tissue Injury ◽  
Human Leukocyte ◽  
Cell Surface Expression ◽  
Human Monocytes ◽  
Leukocyte Elastase ◽  
Hla Dr ◽  
High Level

We have demonstrated that a discrete and naturally occurring subpopulation of human monocytes expresses a neutrophil-like proinflammatory (P) phenotype. P monocytes constitute 20-30% of the circulating monocyte pool and are characterized by 1) avid adherence to extracellular matrix through high-level cell-surface expression of alpha 5-, beta 1-, and beta 2-integrins; 2) high capacity to produce reactive oxygen species; 3) high content of serine proteinases and alpha 1-proteinase inhibitor; and 4) proteolytic activity against a soluble peptide human leukocyte elastase substrate, [3H]elastin, and solid-phase fibronectin, even in the presence of proteinase inhibitors. However, P monocytes express little or no cell-surface HLA-DR antigen, suggesting that they are unable to participate in specific immune responses. In contrast, the remainder of circulating monocytes have a low proinflammatory potential but contain the population of monocytes with high-level expression of HLA-DR antigen. P monocytes can readily be separated from the remainder of monocytes on the basis of 1) their capacity to adhere to fibronectin; and 2) their absent expression of HLA-DR antigen when flow cytometry or immunomagnetic beads are used. Our data indicate that, when recruited to sites of inflammation, P monocytes can either promote resolution of inflammation or contribute to tissue injury.

scholarly journals Cell surface-bound elastase and cathepsin G on human neutrophils: a novel, non-oxidative mechanism by which neutrophils focus and preserve catalytic activity of serine proteinases.

1995 ◽  
Vol 131 (3) ◽  
pp. 775-789 ◽  
Author(s):  
C A Owen ◽  
M A Campbell ◽  
P L Sannes ◽  
S S Boukedes ◽  
E J Campbell
Keyword(s):  
Cell Surface ◽  
Proteinase Inhibitors ◽  
Human Leukocyte ◽  
Surface Expression ◽  
Cathepsin G ◽  
Cell Surface Expression ◽  
Human Neutrophils ◽  
Serine Proteinases ◽  
Leukocyte Elastase ◽  
Human Leukocyte Elastase

Serine proteinases of human polymorphonuclear neutrophils play an important role in neutrophil-mediated proteolytic events; however, the non-oxidative mechanisms by which the cells can degrade extracellular matrix in the presence of proteinase inhibitors have not been elucidated. Herein, we provide the first report that human neutrophils express persistently active cell surface-bound human leukocyte elastase and cathepsin G on their cell surface. Unstimulated neutrophils have minimal cell surface expression of these enzymes; however, phorbol ester induces a 30-fold increase. While exposure of neutrophils to chemoattractants (fMLP and C5a) stimulates modest (two- to threefold) increases in cell surface expression of serine proteinases, priming with concentrations of lipopolysaccharide as low as 100 fg/ml leads to striking (up to 10-fold) increase in chemoattractant-induced cell surface expression, even in the presence of serum proteins. LPS-primed and fMLP-stimulated neutrophils have approximately 100 ng of cell surface human leukocyte elastase activity per 10(6) cells. Cell surface-bound human leukocyte elastase is catalytically active, yet is remarkably resistant to inhibition by naturally occurring proteinase inhibitors. These data indicate that binding of serine proteinases to the cell surface focuses and preserves their catalytic activity, even in the presence of proteinase inhibitors. Upregulated expression of persistently active cell surface-bound serine proteinases on activated neutrophils provides a novel mechanism to facilitate their egress from the vasculature, penetration of tissue barriers, and recruitment into sites of inflammation. Dysregulation of the cell surface expression of these enzymes has the potential to cause tissue destruction during inflammation.

Cytokines regulate membrane-bound leukocyte elastase on neutrophils: a novel mechanism for effector activity

1997 ◽  
Vol 272 (3) ◽  
pp. L385-L393 ◽  
Author(s):  
C. A. Owen ◽  
M. A. Campbell ◽  
S. S. Boukedes ◽  
E. J. Campbell
Keyword(s):  
Cell Surface ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Human Leukocyte ◽  
Tnf Alpha ◽  
Elastase Activity ◽  
Leukocyte Elastase ◽  
Necrosis Factor Alpha ◽  
Proinflammatory Mediators ◽  
Membrane Bound

Membrane-bound leukocyte elastase activity on neutrophils may have potent proinflammatory effects. Herein, we report the effects of tumor necrosis factor-alpha (TNF-alpha), platelet-activating factor (PAF), N-formyl-leucyl-methionyl-phenylalanine (fMLP), and interleukin-8 (IL-8) on membrane-bound elastase expression. TNF-alpha or PAF alone induced only approximately two- to threefold increases in membrane-bound elastase but exhibited marked dose- and time-dependent priming effects for subsequent stimulation with fMLP or IL-8 (up to 20-fold increases in membrane-bound human leukocyte elastase compared with unstimulated cells). Optimally PAF-primed and fMLP-stimulated cells expressed 1.105 +/- 0.25 (SD) x 10(-17) mol [6.65 +/- 1.51 (SD) x 10(6) molecules] membrane-bound elastase activity/cell or approximately 12% of the content of unstimulated cells. Elastase binds to the cell surface by a charge-dependent mechanism since 1) incubation of cells with cationic molecules abrogated agonist-induced upregulation of membrane-bound elastase and 2) elastase was progressively eluted from the cell surface by solutions with increasing ionic strength. Thus interactions between proinflammatory mediators strikingly upregulate membrane-bound elastase on neutrophils, which may promote inflammatory responses and/or contribute to tissue injury.

scholarly journals Bordetella pertussis Infection of Primary Human Monocytes Alters HLA-DR Expression

2004 ◽  
Vol 72 (3) ◽  
pp. 1450-1462 ◽  
Author(s):  
Jennifer A. Shumilla ◽  
Vashti Lacaille ◽  
Tara M. C. Hornell ◽  
Jennifer Huang ◽  
Supraja Narasimhan ◽  
...  
Keyword(s):  
Cell Surface ◽  
Bordetella Pertussis ◽  
Whooping Cough ◽  
Surface Expression ◽  
Interleukin 10 ◽  
Cell Surface Expression ◽  
Human Monocytes ◽  
Pertussis Infection ◽  
Hla Dr ◽  
Ifn Γ

ABSTRACT Bordetella pertussis is the causative agent of whooping cough, a potentially lethal respiratory disease in children. In immunocompetent individuals, B. pertussis infection elicits an effective adaptive immune response driven by activated CD4+ T cells. However, live B. pertussis persists in the host for 3 to 4 weeks prior to clearance. Thus, B. pertussis appears to have evolved short-term mechanisms for immune system evasion. We investigated the effects of B. pertussis wild-type strain BP338 on antigen presentation in primary human monocytes. BP338 infection reduced cell surface expression of HLA-DR and CD86 but not that of major histocompatibility complex class I proteins. This change in cell surface HLA-DR expression reflected intracellular redistribution of HLA-DR. The proportion of peptide-loaded molecules was unchanged in infected cells, suggesting that intracellular retention occurred after peptide loading. Although B. pertussis infection of monocytes induced rapid and robust expression of interleukin-10 (IL-10), HLA-DR redistribution did not appear to be explained by increased IL-10 levels. BP338-infected monocytes exhibited reduced synthesis of HLA-DR dimers. Interestingly, those HLA-DR proteins that were generated appeared to be longer-lived than HLA-DR in uninfected monocytes. BP338 infection also prevented gamma interferon (IFN-γ) induction of HLA-DR protein synthesis. Using mutant strains of B. pertussis, we found that reduction in HLA-DR surface expression was due in part to the presence of pertussis toxin whereas the inhibition of IFN-γ induction of HLA-DR could not be linked to any of the virulence factors tested. These data demonstrate that B. pertussis utilizes several mechanisms to modulate HLA-DR expression.

scholarly journals Slow Human Immunodeficiency Virus (HIV) Infectivity Correlated with Low HIV Coreceptor Levels

2001 ◽  
Vol 8 (5) ◽  
pp. 932-936 ◽  
Author(s):  
Cynthia L. Bristow
Keyword(s):  
Human Immunodeficiency Virus ◽  
Cell Surface ◽  
Chemokine Receptors ◽  
Surface Density ◽  
Human Leukocyte ◽  
Absolute Number ◽  
Mononuclear Phagocytes ◽  
Leukocyte Elastase ◽  
Immunodeficiency Virus

ABSTRACT The absolute number of CD4+ lymphocytes in blood is prognostic for disease progression, yet the cell surface density of CD4 receptors or chemokine receptors on a single cell has not previously been found to be predictive of human immunodeficiency virus (HIV) infectivity outcome. It has recently been shown that human leukocyte elastase (HLE) and its ligand α1 proteinase inhibitor (α1PI; α1 antitrypsin) act as HIV fusion cofactors. The present study shows that decreased HIV infectivity is significantly correlated with decreased cell surface density of HLE but not with decreased CD4 nor chemokine receptors. In vitro HIV infectivity outcome in this study was predicted by the surface density of HLE on mononuclear phagocytes but not on lymphocytes. The set point HLE surface density was in part determined by α1PI. Decreased circulating α1PI was correlated with increased cell surface HLE and with increased HIV infectivity. The correlation of HIV infectivity outcome with surface HLE and circulating α1PI supports the utility of these HIV cofactors in diagnostic analysis and therapeutic intervention.

scholarly journals Cell Surface Expression and Function of the Macromolecular C1 Complex on the Surface of Human Monocytes

2012 ◽  
Vol 3 ◽  
Author(s):  
Kinga K. Hosszu ◽  
Alisa Valentino ◽  
Yan Ji ◽  
Mara Matkovic ◽  
Lina Pednekar ◽  
...  
Keyword(s):  
Cell Surface ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Human Monocytes ◽  
And Function

Metalloproteinases Are Involved in Lipopolysaccharide– and Tumor Necrosis Factor-–Mediated Regulation of CXCR1 and CXCR2 Chemokine Receptor Expression

Blood ◽  
1999 ◽  
Vol 93 (7) ◽  
pp. 2173-2185 ◽  
Author(s):  
Masud H. Khandaker ◽  
Gordon Mitchell ◽  
Luoling Xu ◽  
Joseph D. Andrews ◽  
Rajkumari Singh ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Cell Surface ◽  
Tumor Necrosis ◽  
Inflammatory Responses ◽  
Proteinase Inhibitors ◽  
Surface Expression ◽  
Receptor Expression ◽  
Cell Surface Expression ◽  
Metalloproteinase Inhibitors ◽  
Necrosis Factor

The neutrophil-specific G-protein–coupled chemokine receptors, CXCR1 and CXCR2, bind with high affinity to the potent chemoattractant interleukin-8 (IL-8). The mechanisms of IL-8 receptor regulation are not well defined, although previous studies have suggested a process of ligand-promoted internalization as a putative regulatory pathway. Herein, we provide evidence for two distinct processes of CXCR1 and CXCR2 regulation. Confocal microscopy data showed a redistribution of CXCR1 expression from the cell surface of neutrophils to internal compartments after stimulation with IL-8, whereas stimulation with bacterial lipopolysaccharide (LPS) or tumor necrosis factor- (TNF-) did not induce CXCR1 internalization but instead mediated a significant loss of membrane-proximal CXCR1 staining intensity. To investigate whether proteolytic cleavage was the mechanism responsible for LPS- and TNF-–induced downmodulation of IL-8 receptors, we tested a panel of proteinase inhibitors. The downmodulation of CXCR1 and CXCR2 by LPS and TNF- was most dramatically inhibited by metalloproteinase inhibitors; 1,10-phenanthroline and EDTA significantly attenuated LPS- and TNF-–induced loss of CXCR1 and CXCR2 cell surface expression. Metalloproteinase inhibitors also blocked the release of CXCR1 cleavage fragments into the cell supernatants of LPS- and TNF-–stimulated neutrophils. In addition, while treatment of neutrophils with LPS and TNF- inhibited IL-8 receptor–mediated calcium mobilization and IL-8–directed neutrophil chemotaxis, both 1,10-phenanthroline and EDTA blocked these inhibitory processes. In contrast, metalloproteinase inhibitors did not affect IL-8–mediated downmodulation of CXCR1 and CXCR2 cell surface expression or receptor signaling. Thus, these findings may provide further insight into the mechanisms of leukocyte regulation during immunologic and inflammatory responses.

scholarly journals Neutral protease secretion by human monocytes. Effect of surface-bound immune complexes.

1979 ◽  
Vol 149 (4) ◽  
pp. 954-968 ◽  
Author(s):  
C G Ragsdale ◽  
W P Arend
Keyword(s):  
Plasminogen Activator ◽  
Immune Complexes ◽  
Tissue Injury ◽  
Polymorphonuclear Neutrophils ◽  
Human Monocytes ◽  
Leukocyte Elastase ◽  
Fibrinolytic Enzymes ◽  
Protease Secretion ◽  
Neutral Proteases ◽  
Effect Of Surface

The effect of surface-bound immune complexes on the secretion of neutral proteases by human peripheral monocytes was examined. Monocytes cultured on 125I-fibrin secreted plasminogen activator in a continuous fashion. Monocytes incubated on 125I-fibrin with surface-bound immune complexes displayed a burst of plasminogen-independent fibrinolytic activity, whereas no release of plasminogen activator was observed through 21 h. The plasminogen-independent fibrinolytic enzymes were derived from monocytes and not from lymphocytes or contaminating polymorphonuclear neutrophils. The effects of various protease inhibitors on the secretion of plasminogen-dependent and independent enzymes were determined. Chymostatin selectively inhibited the monocyte-derived plasminogen activators. Similar effects of chymostatin were observed on human urokinase in the absence of cells. The predominant protease producing plasminogen-independent fibrinolysis exhibited responses to inhibitors characteristic of leukocyte elastase. When monocytes were cultured on 125I-fibrin with adherent immune complexes approximately equal to 40% of the solubilized radioactivity represented deiodination and not proteolysis. It was concluded that culture of human monocytes on surface-bound immune complexes stimulates the secretion of plasminogen-independent fibrinolytic proteases, primarily elastase, and of deiodinating enzymes. Under these conditions, plasminogen activator secretion is inhibited. Neutral proteases secreted from newly recruited monocytes may contribute to tissue injury in human diseases characterized by the presence of adherent immune complexes.

HIV-1 preferentially binds receptors copatched with cell-surface elastase

Blood ◽  
2003 ◽  
Vol 102 (13) ◽  
pp. 4479-4486 ◽  
Author(s):  
Cynthia L. Bristow ◽  
Danielle R. Mercatante ◽  
Ryszard Kole
Keyword(s):  
Cell Surface ◽  
Proteinase Inhibitor ◽  
Human Leukocyte ◽  
Dose Dependence ◽  
Hiv Disease ◽  
Leukocyte Elastase ◽  
Human Leukocyte Elastase ◽  
Hiv Seropositive ◽  
Hiv 1 ◽  
Recent Demonstration

Abstract Human leukocyte elastase (HLE) interacts with HIV-1 glycoprotein (gp)41, suggesting a nonenzymatic receptor function for HLE in the context of HIV-1. HLE is found localized to the cell surface, but not granules in HIV permissive clones, and to granules, but not the cell surface of HIV nonpermissive clones. Inducing cell-surface HLE expression on HLE null, HIV nonpermissive clones permits HIV infectivity. HIV binding and infectivity diminish in proportion to HLE RNA subtraction. HIV binding and infectivity show dose dependence for the natural HLE ligand α1 proteinase inhibitor (α1antitrypsin, α1PI). Chemokines prevent, whereas α1PI promotes, copatching of HLE with the canonical HIV receptors. Recent demonstration that decreased viral RNA is significantly correlated with decreased circulating α1PI in HIV seropositive individuals is consistent with a model in which HLE and α1PI can serve as HIV coreceptor and cofactor, respectively, and potentially participate in the pathophysiology of HIV disease progression. (Blood. 2003;102:4479-4486)

scholarly journals Human cytomegalovirus suppresses Fas expression and function

2014 ◽  
Vol 95 (4) ◽  
pp. 933-939 ◽  
Author(s):  
Sepehr Seirafian ◽  
Virginie Prod’homme ◽  
Daniel Sugrue ◽  
James Davies ◽  
Ceri Fielding ◽  
...  
Keyword(s):  
Cell Surface ◽  
Human Cytomegalovirus ◽  
De Novo ◽  
Late Phase ◽  
Surface Expression ◽  
Productive Infection ◽  
Cell Surface Expression ◽  
Trail Receptor ◽  
Infected Cells ◽  
High Level

Human cytomegalovirus (HCMV) is known to evade extrinsic pro-apoptotic pathways not only by downregulating cell surface expression of the death receptors TNFR1, TRAIL receptor 1 (TNFRSF10A) and TRAIL receptor 2 (TNFRSF10B), but also by impeding downstream signalling events. Fas (CD95/APO-1/TNFRSF6) also plays a prominent role in apoptotic clearance of virus-infected cells, so its fate in HCMV-infected cells needs to be addressed. Here, we show that cell surface expression of Fas was suppressed in HCMV-infected fibroblasts from 24 h onwards through the late phase of productive infection, and was dependent on de novo virus-encoded gene expression but not virus DNA replication. Significant levels of the fully glycosylated (endoglycosidase-H-resistant) Fas were retained within HCMV-infected cells throughout the infection within intracellular membranous structures. HCMV infection provided cells with a high level of protection against Fas-mediated apoptosis. Downregulation of Fas was observed with HCMV strains AD169, FIX, Merlin and TB40.

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