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Biomedical subjects

R van Furth

Publications and source records attributed to R van Furth.

At least 73 records · Page 4Linked to original sources
PubMed1994

Protein tyrosine kinase activity is essential for Fc gamma receptor-mediated intracellular killing of Staphylococcus aureus by human monocytes.

Our previous study revealed that the intracellular killing of Staphylococcus aureus by human monocytes after cross-linking Fc gamma receptor I (Fc gamma RI) or Fc gamma RII is a phospholipase C (PLC)-dependent process. The aim of the present study was to investigate whether protein tyrosine kinase (PTK) activity plays a role in the Fc gamma R-mediated intracellular killing of bacteria and activation of PLC in these cells. The results showed that phagocytosis of bacteria by monocytes was not affected by the PTK inhibitors genistein and tyrphostin-47. The intracellular killing of S. aureus by monocytes after cross-linking Fc gamma RII or Fc gamma RII with anti-Fc gamma R monoclonal antibody and a bridging antibody or with human immunoglobulin G (IgG) was inhibited by these compounds in a dose-dependent fashion. The production of O2- by monocytes after stimulation with IgG or IgG-opsonized S. aureus was almost completely blocked by the PTK inhibitor. These results indicate that inhibition of PTK impairs the oxygen-dependent bactericidal mechanisms of monocytes. Genistein and tyrphostin-47, which do not affect the enzymatic activity of purified PLC, prevented activation of PLC after cross-linking Fc gamma RI or Fc gamma RII, measured as an increase in the intracellular inositol 1,4,5-trisphosphate concentration. Cross-linking Fc gamma RI or Fc gamma RII induced rapid tyrosine phosphorylation of several proteins in monocytes, one of which was identified as PLC-gamma 1, and the phosphorylation could be completely blocked by PTK inhibitors, leading to the conclusion that activation of PLC after cross-linking Fc gamma R in monocytes is regulated by PTK activity. Together, these results demonstrate that PTK activity is essential for the activation of PLC which is involved in the Fc gamma R-mediated intracellular killing of S. aureus by human monocytes.

Blood Bactericidal Activity↗
PubMed1994

Virulence factors determine attachment and ingestion of nonopsonized and opsonized Bordetella pertussis by human monocytes.

In the present study, the role of virulence factors in and the effect of opsonization on the interactions between Bordetella pertussis and human monocytes were investigated. The methods used facilitated the distinction between attachment and ingestion of bacteria by monocytes. Nonopsonized virulent B. pertussis cells attached to monocytes. Nonopsonized B. pertussis mutant strains deficient in filamentous hemagglutinin, fimbriae, or pertactin exhibited a reduced adherence to monocytes compared with that of their respective parental strains. Nonopsonized avirulent B. pertussis cells did not attach to monocytes. These results led to the conclusion that fimbriae and pertactin are involved in the adherence of nonopsonized virulent B. pertussis cells to monocytes and confirm the role of filamentous hemagglutinin in this process. In the absence of opsonins, about 40% of the monocyte-associated virulent B. pertussis cells were ingested. When B. pertussis cells were preopsonized with inactivated normal serum, about 50% of the monocyte-associated virulent B. pertussis cells were phagocytosed and about 80% of the monocyte-associated avirulent B. pertussis cells were ingested. These results indicate that virulence factors inhibit opsonin-mediated ingestion of B. pertussis by monocytes.

Antibodies, Bacterial↗
PubMed1994

Granulocyte-macrophage colony-stimulating factor is not involved in production of reactive nitrogen intermediates by or toxoplasmastatic activity of gamma interferon-activated murine macrophages.

The induction of reactive nitrogen intermediates (RNI) and toxoplasmastatic activity of murine macrophages by recombinant gamma interferon (rIFN-gamma) is mediated by an autocrine pathway involving tumor necrosis factor alpha (TNF-alpha). To investigate whether cytokines other than TNF-alpha play a role in the activation of these effector functions, granulocyte-macrophage colony-stimulating factor (GM-CSF) was studied. Recombinant GM-CSF (rGM-CSF) could stimulate peritoneal macrophages, since this cytokine stimulated the production of prostaglandin E2 by these cells. However, rGM-CSF did not induce either the release of RNI by or the toxoplasmastatic activity of macrophages. rGM-CSF in combination with various concentrations of rIFN-gamma did not enhance these effector functions more than rIFN-gamma alone. Furthermore, neutralization of endogenously produced GM-CSF by monoclonal antibodies did not affect the release of RNI by or the toxoplasmastatic activity of rIFN-gamma-activated macrophages. Together these results indicate that GM-CSF is not involved in RNI production by and toxoplasmastatic activity of IFN-gamma-activated murine macrophages.

Animals↗
PubMed1994

Binding of surfactant protein A to C1q receptors mediates phagocytosis of Staphylococcus aureus by monocytes.

During both steady-state conditions and inflammatory reactions in the lower airways, monocytes migrate to the alveoli where they come into contact with surfactant. Surfactant is composed of phospholipids, neutral lipids, and specific proteins, and its main function is to reduce surface tension in the alveoli. The most abundant glycoprotein surfactant protein A (SP-A) affects the structure, function, and metabolism of pulmonary surfactant. The aim of the present study was to determine whether SP-A plays a role in the antibacterial activities of human monocytes and whether this is mediated by a receptor for SP-A on these cells. The results showed that SP-A binds to both Staphylococcus aureus and monocytes and mediates the phagocytosis of the bacteria by these cells. SP-A does not stimulate the intracellular killing of bacteria by monocytes, and SP-A-opsonized S. aureus do not induce the production of reactive oxygen intermediates. SP-A binds to the C1q receptor (C1qR) on monocytes, since its binding was inhibited by C1q and the SP-A-enhanced association of S. aureus with these cells was completely abolished when monocytes were adherent to surfaces coated with C1q or anti-C1qR monoclonal antibody. Furthermore, the binding of SP-A to monocytes results in an increased intracellular concentration of adenosine 3',5'-cyclic monophosphate. Together, these results demonstrate that C1qR mediates the phagocytosis of SP-A-opsonized S. aureus by monocytes.

Calcium↗
PubMed1994

In vitro effect of dexamethasone, pentoxifylline, and anti-endotoxin monoclonal antibody on the release of proinflammatory mediators by human leukocytes stimulated with Haemophilus influenzae type B.

The effects of dexamethasone, pentoxifylline, and MAb against endotoxin (HA-1A) on the release of various proinflammatory mediators, i.e. tumor necrosis factor-alpha (TNF), IL-1 beta, IL-8, and prostaglandin 2, by human leukocytes during stimulation with Haemophilus influenzae type B were studied. The results show that only monocytes, and thus neither lymphocytes nor granulocytes, release these mediators in response to H. influenzae. Dexamethasone inhibited the release of all of these mediators, whereas pentoxifylline only inhibited the release of TNF. HA-1A only reduced the release of IL-8 from adherent monocytes significantly and had no significant effect on the release of TNF, IL-1 beta, and prostaglandin E2. In whole blood, no significant effect of HA-1A on the release of TNF, IL-1 beta, IL-8, and prostaglandin E2 was found. In summary, the results of this study demonstrate that dexamethasone is the most potent inhibitor of the release of proinflammatory mediators by monocytes induced by H. influenzae type B.

Antibodies, Monoclonal↗
PubMed1994

Pulmonary surfactant inhibits monocyte bactericidal functions by altering activation of protein kinase A and C.

Pulmonary surfactant, the main function of which is to reduce surface tension in the alveoli, is also known to affect the functions of monocytes. Two protein kinases play a role in the regulation of the bactericidal functions of phagocytes, i.e. cAMP-dependent protein kinase A (PKA), which is involved in inhibition, and Ca2+/phospholipid-dependent PKC, which is involved in stimulation of these functions. In the present study we investigated whether altered activation of PKA and/or PKC plays a role in the surfactant-induced inhibition of both the intracellular killing of Staphylococcus aureus and the production of reactive oxygen intermediates (ROI) by monocytes. The significance of increased activation of PKA was demonstrated by the following findings. Firstly, surfactant induced a sustained increase in the intracellular cAMP concentration in monocytes. Secondly, dibutyryl-cAMP (db-cAMP), a membrane-permeable cAMP analogue, mimicked the inhibitory effects of surfactant on both the killing capacity and the production of ROI by monocytes. Thirdly, an inhibitor of PKA partially restored the impaired bactericidal functions of monocytes incubated with surfactant. The involvement of decreased activation of PKC in the impaired bactericidal functions of monocytes incubated with surfactant was evident from two findings. Firstly, surfactant attenuated the phorbol myristate acetate (PMA)-mediated translocation of PKC. Secondly, surfactant inhibited the production of O2- by monocytes upon stimulation with PMA. Therefore, the mechanism involved in the surfactant-induced inhibition of the bactericidal functions of monocytes comprises both activation of an inhibitory pathway, which includes cAMP and PKA, and inactivation of a stimulatory pathway, in which PKC is involved.

Bucladesine↗
PubMed1994

Effect of IFN-gamma on the proliferation of Toxoplasma gondii in monocytes and monocyte-derived macrophages from AIDS patients.

This study was undertaken to determine whether the activity of monocytes and monocyte-derived macrophages (MDM) from acquired immune deficiency syndrome (AIDS) patients against Toxoplasma gondii is altered and whether this activity can be modulated by recombinant interferon-gamma (rIFN-gamma). Untreated and rIFN-gamma-treated monocytes or MDM from AIDS patients and from healthy controls were infected with T. gondii and the proliferation of these protozoa was determined. The H2O2 release by monocytes from AIDS patients and healthy controls was measured upon stimulation with phorbol myristate acetate (PMA) and formyl methionyl leucyl phenylalanine (FMLP). Monocytes from AIDS patients exhibited significantly lower toxoplasmastic activity compared to monocytes from healthy controls. The H2O2 release by monocytes from AIDS patients was also diminished. Incubation of monocytes from AIDS patients with rIFN-gamma for 2 days, but not 1 day, restored their toxoplasmastatic activity. The rate of proliferation of T. gondii was higher in MDM from AIDS patients than in MDM from healthy controls. Treatment of MDM from AIDS patients with rIFN-gamma for 1, 2 or 3 days resulted in partial inhibition of the proliferation of T. gondii. Collectively, these results demonstrate that the reduced toxoplasmastatic activity of monocytes and MDM from AIDS patients can be enhanced by in vitro treatment with rIFN-gamma, which supports the clinical use of rIFN-gamma for the treatment of opportunistic infections in these patients.

AIDS-Related Opportunistic Infections↗
PubMed1994

Pulmonary surfactant inhibits activation of human monocytes by recombinant interferon-gamma.

During an inflammatory reaction in the alveoli, the functional activities of monocytes, macrophages and granulocytes are regulated by a complex network of inflammatory mediators. The primary cytokine involved in activation of these phagocytes is interferon-gamma (IFN-gamma). The possible influence of local factors, such as pulmonary surfactant, on the activation process has not been studied until now. The aim of the present study was to investigate the effects of surfactant on the activation of monocytes by recombinant (r)IFN-gamma. The results revealed that human surfactant significantly inhibited both the increase in the expression of the high-affinity receptor for IgG, i.e. Fc gamma RI, and the production of H2O2 by rIFN-gamma-activated monocytes. Since our surfactant preparation stimulated the basal production of tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) by monocytes, the effect of Survanta, a surfactant extract, on the rIFN-gamma-induced production of these cytokines by monocytes was studied. The results revealed that Survanta caused 80-90% inhibition of the rIFN-gamma-induced production of TNF-alpha and IL-1 beta by these cells. Together, these results could mean that surfactant is involved in the protection of the alveolar epithelium against injury caused by reactive oxygen intermediates (ROI) and TNF-alpha, and in the down-regulation of the production of inflammatory mediators. In view of these considerations, surfactant therapy may not only improve lung compliance and gas exchange but may also be beneficial in reducing the inflammatory reaction in the lungs.

Biological Products↗
PubMed1994

Prevention of nosocomial spread of multidrug-resistant tubercle bacilli.

Outbreaks of multidrug-resistant Mycobacterium tuberculosis (multidrug-resistant tuberculosis; MDR-TB) have recently been reported in hospitals in the United States. Rapid spread of these bacilli and a high mortality among immunocompromised patients, i.e. HIV-infected individuals and AIDS patients, were observed. Factors that play a role in these outbreaks and the prevention of MDR-TB are discussed in this article. Awareness of a possible M. tuberculosis infection and the early introduction of measures to reduce the spread of these micro-organisms are steps that can prevent a nosocomial outbreak. The use of more rapid methods for culturing mycobacteria and determining their sensitivity to antimicrobial drugs can accelerate the diagnostic process and the recognition of multiresistance. In view of the poor results of treatment of MDR-TB, prevention should be the first requirement.

Cross Infection↗
PubMed1994

Effect of IFN-gamma and endogenous TNF on the histopathological changes in the liver of Listeria monocytogenes-infected mice.

During primary infection of mice with Listeria monocytogenes, the bacteria proliferate extensively in the liver resulting in the development of inflammatory lesions in this organ. In the present study, the effect of interferon-gamma (IFN-gamma) on the development of these lesions, and the involvement of endogenous tumour necrosis factor-alpha (TNF-alpha) in the IFN-gamma-induced effects were evaluated. During an infection of naive mice with L. monocytogenes, two types of inflammatory lesions in the liver could be distinguished: large necrotic lesions consisting of granulocytes and/or exudate macrophages and small lesions containing mainly mature macrophages, i.e. BM8-expressing cells. Necrotic lesions were characterized by the presence of CD11b-expressing cells and consisted mainly of granulocytes during days 1 and 2 of infection and thereafter of exudate macrophages. The lesions consisting of mature macrophages and lymphocytes were not associated with necrosis and were called granulomatous lesions. Some of the granulomatous lesions contained many cells that expressed Ia antigen, i.e. activated cells. Treatment of mice with recombinant (r)IFN-gamma before injection of L. monocytogenes resulted in a decrease in the number of necrotic lesions and an increase in the number of granulomatous lesions in the liver, which was accompanied by a reduced bacterial proliferation in the liver. The effect of rIFN-gamma on the development of the various types of inflammatory lesions in the liver during infection with L. monocytogenes was abrogated by anti-TNF-alpha antibody and this antibody abrogated the rIFN-gamma-induced reduction of bacterial proliferation in the liver as well. Together, the results demonstrate that endogenous TNF-alpha plays a key role in the effects of rIFN-gamma on the inflammatory response in the liver during an infection with L. monocytogenes.

Animals↗
PubMed1994

Comparison of antibody activity against various microorganisms in intravenous immunoglobulin preparations determined by ELISA and opsonic assay.

In the present study the level of antimicrobial antibodies and the phagocytosis-promoting activity in immunoglobulin preparations produced for intravenous use were assessed. The level of antibodies directed against various microorganisms in six immunoglobulin preparations was determined by using an enzyme-linked immunosorbent assay (ELISA) and was shown to be either equal to or higher than that of pooled normal human serum. All preparations were able to promote phagocytosis of Staphylococcus aureus, Escherichia coli K12, and Streptococcus pyogenes by human granulocytes. Substantial differences among the various preparations in antibody activity were noted. In particular, Intraglobulin, chemically modified by beta-propiolactone treatment, exhibited little activity in both the ELISA and the phagocytosis assay. In contrast, IVIG SRC, Gamimmune, Sandoglobulin (treated at low pH in presence or absence of trace amounts of pepsin), and Gammagard (treated by ion-exchange chromatography) showed good activity in both assays. Comparison of the results of the ELISA and phagocytosis assay for the various preparations indicated a good correlation except for S. aureus with a moderate (strain 42D) or high (strain Cowan I) protein A content. These data indicate that the antibody activity of immunoglobulin preparations against various microorganisms determined by ELISA can be used to predict their opsonic activity.

Antibodies, Bacterial↗
PubMed1993

Very late antigen-5 and complement receptor type 3 cooperatively mediate the interaction between Bordetella pertussis and human monocytes.

Nonopsonized Bordetella pertussis, the causative agent of whooping cough, can attach to and become ingested by human monocytes. It has been reported that complement receptor type 3 (CR3) on human monocyte-derived macrophages binds filamentous hemagglutinin expressed on B. pertussis. In the present study, the role of very late antigen-5 (VLA-5) in the attachment of B. pertussis to adherent human monocytes was investigated. It was found that soluble fibronectin and soluble mAb against VLA-5 markedly inhibited the attachment of B. pertussis to monocytes. When VLA-5 on monocytes was cross-linked by plating these cells onto surfaces precoated with fibronectin or mAb against VLA-5, the binding of both B. pertussis and C3bi-coated sheep erythrocytes to these cells was significantly enhanced, whereas the binding of a B. pertussis mutant strain deficient in filamentous hemagglutinin was not affected. The enhanced attachment of B. pertussis to monocytes plated onto fibronectin-coated surfaces was markedly inhibited by soluble mAb against CR3. Neutrophils, which express similar levels of CR3 and about 10-fold lower levels of VLA-5 as compared with monocytes, did not bind B. pertussis. Together, these results indicate that VLA-5 is involved in the attachment of B. pertussis to monocytes and that cross-linking of VLA-5 enhances the attachment of B. pertussis to monocytes by augmenting the binding activity of CR3. We propose that the attachment of B. pertussis to monocytes occurs in two steps: binding and cross-linking of VLA-5 by B. pertussis enhances the binding activity of CR3, which in turn facilitates the subsequent binding of these bacteria to the latter receptor.

Adhesins, Bacterial↗
PubMed1993

Lung surfactant suppresses oxygen-dependent bactericidal functions of human blood monocytes by inhibiting the assembly of the NADPH oxidase.

Surfactant is known to lower the surface tension in alveoli and affects the antibacterial functions of alveolar and peritoneal macrophages. We investigated the effects of surfactant on the bactericidal functions and oxidative metabolism of human blood monocytes and granulocytes. Monocytes incubated with surfactant ingest this material and subsequently exhibit an impaired ability to kill ingested bacteria. Granulocytes incubated with surfactant do not ingest this material, and their bactericidal functions are not affected. However, granulocytes that have ingested surfactant-coated Staphylococcus aureus display an impaired ability to kill these bacteria. Moreover, in monocytes and granulocytes that contain surfactant--the latter by ingestion of surfactant-coated S. aureus--the intracellular production of H2O2 is impaired due to inhibition of the assembly of the NADPH oxidase. Together these results demonstrate that surfactant inside monocytes and granulocytes inhibits the capacity of these cells to kill bacteria intracellularly by impairing oxygen-dependent killing mechanisms.

Blood Bactericidal Activity↗
PubMed1993

Cross-linking of CD14 molecules on monocytes results in a CD11/CD18- and ICAM-1-dependent adherence to cytokine-stimulated human endothelial cells.

The myeloid differentiation protein CD14 that is expressed on the surface of mature monocytes contributes to the adherence of monocytes to cytokine-stimulated monolayers of human macrovascular endothelial cells (EC). It has also been observed that the initial adherence of monocytes to cultured cytokine-stimulated EC eventually results in an ICAM-1- and LFA-1 (CD11a/CD18)-dependent adherence, which coincides with stretching and lateral migration of the monocytes over the surface of EC. Recently, it was reported that CD14 mediates monocyte activation and can induce a change in the avidity of CD11a/CD18 for its ligand ICAM-1. The aim of the present study was to investigate whether activation of monocytes by CD14 elicits a CD11/CD18-dependent adhesion of monocytes to ICAM-1 on rIL-1 alpha-stimulated EC. Incubation of monocytes with murine anti-CD14 mAb alone did not mobilize intracellular calcium but the subsequent addition of F(ab')2 anti-mouse Ig, which caused cross-linking of CD14 on the surface of monocytes, induced a transient rise in cytosolic free calcium concentration and enhanced the percentage monocytes that adhered to monolayers of macrovascular venous EC stimulated with rIL-1 alpha for 24 h, but not to nonstimulated EC. The elevated adhesion was decreased with monocytes were preincubated with staurosporine, an inhibitor of intracellular protein kinase activity and was markedly inhibited by mAb against the common beta 2-subunit (CD18) of the CD11/CD18 molecules on monocytes and by mAb against ICAM-1 on 24-h rIL-1 alpha-stimulated venous EC. These studies provide evidence for the hypothesis that the binding of monocytes via CD14 to rIL-1 alpha-stimulated EC generates an intracellular response in monocytes and triggers an adhesion mechanism that allows CD11/CD18 molecules on monocytes to bind to ICAM-1 on EC.

Alkaloids↗