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Biomedical subjects

L Koenderman

Publications and source records attributed to L Koenderman.

At least 73 records · Page 4Linked to original sources
PubMed1997

Neutrophil adhesion to fibrinogen and fibrin under flow conditions is diminished by activation and L-selectin shedding.

The adhesion of neutrophils (polymorphonuclear leukocytes [PMNs]) to immobilized fibrinogen/fibrin is mediated by beta2-integrins. However, the influence of physiologic flow conditions on neutrophil adhesion to these surfaces is poorly defined. In this report, the effect of flow and neutrophil activation on adhesion to immobilized fibrinogen and fibrin was examined. For the evaluation of (the distribution of) neutrophil adhesion, real-time video-assisted microscopy and custom-made software were used. Under flow conditions, adherent neutrophils appeared to support the subsequent margination of other neutrophils, thereby enhancing the adherence of these cells to fibrin. Consequently, neutrophils adhered in clusters, especially at higher shear stresses (eg, cluster index 1.4 at shear 80 mPa). Preactivation of PMNs with fMLP (10(-7) mol/L) or 4beta-phorbol, 12-myristate, 13-acetate (PMA; 100 ng/mL) resulted in approximately 50% inhibition of adhesion to fibrin and a more random distribution (cluster index <0.5). L-selectin antibodies or neuraminidase treatment of PMNs also inhibited adhesion and clustering, indicating a role for L-selectin. Under static conditions, no clustering appeared and PMN activation with fMLP or PMA caused threefold and sevenfold increased adhesion, respectively. Under these conditions, anti-L-selectin antibodies or neuraminidase did not affect adhesion. These results indicate that, under flow conditions, adherent neutrophils support adhesion of flowing neutrophils by L-selectin-mediated cell-cell interactions. Preactivated neutrophils, with lowered L-selectin expression, are less susceptible for this interaction. By this mechanism, adhered leukocytes can modulate the recruitment of leukocytes to the vessel wall at sites of inflammation.

Cell Adhesion↗
PubMed1997

Activation of 12-O-tetradecanoylphorbol-13-acetate response element- and dyad symmetry element-dependent transcription by interleukin-5 is mediated by Jun N-terminal kinase/stress-activated protein kinase kinases.

Interleukin-5 (IL-5) is one of the major regulators of eosinophilic granulocytes in vivo. IL-5 exerts its pleiotropic effects by binding to the IL-5 receptor, which is composed of an IL-5-specific alpha chain and a common betac chain shared with the receptors for IL-3 and granulocyte-macrophage colony-stimulating factor. Previous studies have shown that binding of IL-5 to its receptor triggers the activation of multiple signaling cascades, including the Ras/mitogen-activated protein kinase, the phosphatidyl -3'-kinase, and the Janus kinase/signal transducer and activator of transcription pathways. Here we describe that IL-5 activates the serine/threonine protein kinase Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) pathway. We show that IL-5 activates TPA response element (TRE)-dependent transcription in transfection experiments. TRE activation by IL-5 is mediated by a region of the betac (577-581) that is also responsible for activation of JNK/SAPK and for activation of dyad symmetry element (DSE)-dependent transcription. Dominant-negative SAPK or ERK kinase-1 was used to demonstrate that JNK/SAPK activation is necessary for induction of DSE- and TRE-dependent transcription by IL-5, whereas extracellular signal-regulated kinase 2 was not essential for TRE- and DSE-dependent transcription. By contrast, IL-5-induced activation of the tyrosine kinase Janus kinase 2 seems to be a prerequisite for TRE- and DSE-dependent transcription. Taken together, we show for the first time that IL-5 activates kinases of the JNK/SAPK family, and that this activation is linked to IL-5-induced TRE- and DSE-dependent transcription.

Animals↗
PubMed1997

Platelet and fibrin deposition at the damaged vessel wall: cooperative substrates for neutrophil adhesion under flow conditions.

At sites of vessel wall damage, the primary hemostatic reaction involves platelet and fibrin deposition. At these sites, circulating leukocytes marginate and become activated. Adhered platelets can support leukocyte localization; however, the role of fibrin in this respect is not known. We studied the adhesion of human neutrophils (polymorphonuclear leukocytes [PMNs]) to endothelial extracellular matrix (ECM)-bound fibrin and platelets under flow conditions. ECM alone did not show PMN adhesion. ECM-coated cover slips were perfused with plasma to form a surface-bound fibrin network, and/or with whole blood to allow platelet adhesion. Unstimulated PMNs adhered to fibrin at moderate shear stress (20 to 200 mPa). ECM-bound platelets induced rolling adhesion and allowed more PMNs to adhere at higher shear (320 mPa). ECM coated with both platelets and fibrin induced more static and shear-resistant PMN adhesion. PMN adhesion to fibrin alone but not to platelet/fibrin surfaces was inhibited by soluble fibrinogen. Adhesion to fibrin alone was inhibited by CD11b and CD18 blocking antibodies. Furthermore, fibrin formed under flow conditions showed up to threefold higher PMN adhesion compared with fibrin formed under static conditions, due to structural differences. These results indicate that circulating PMNs adhere to fibrin in an integrin-dependent manner at moderate shear stresses. However, at higher shear rates (> 200 mPa), additional mechanisms (ie, activated platelets) are necessary for an interaction of PMNs with a fibrin network.

CD18 Antigens↗
PubMed1997

NF-kappa B/Rel family members regulating the ICAM-1 promoter in monocytic THP-1 cells.

A kappa B-site was identified in the promoter of the intercellular adhesion molecule-1 (ICAM-1) gene, which is involved in regulation of ICAM-1 expression by tumor necrosis factor alpha (TNF-alpha) and glucocorticoids. We now report on the transcription factors which bind and transactivate this enhancer sequence. In vitro, the ICAM-1 kappa B site appeared to bind RelA and c-Rel homodimers as well as heterodimers with NF-kappa B1, but weakly NF-kappa B1 homodimers. In addition, both RelA and c-Rel, but not NF-kappa B1, were shown to transactivate an ICAM-1 kappa B-reporter construct. In monocytic THP-1 cells TNF-alpha induced two nuclear complexes which in vitro bound to the ICAM-1 kappa B site. Using antibodies in an electrophoretic mobility supershift assay, one of these complexes was shown to contain NF-kappa B1 and RelA, and to bind with higher affinity to the consensus kappa B site in the HIV long terminal repeat. The second complex contained RelA, and exhibited higher affinity towards the ICAM-1 kappa B than to the HIV kappa B site. The glucocorticoid receptor was shown to repress activity of both the RelA homodimer and the NF-kappa B1/RelA heterodimer. We argue that in vivo RelA homodimers are likely to play a dominant role in TNF-alpha-induced ICAM-1 transcription in monocytic cells.

Animals↗
PubMed1997

Bronchial and cutaneous responses in atopic dermatitis patients after allergen inhalation challenge.

BACKGROUND: Atopic dermatitis (AD) is often associated with allergic asthma (AA). Inhalation of allergens influences the activity of AA but the effect on the skin in AD is unclear. OBJECTIVES: We evaluated the degree of bronchial hyperresponsiveness to methacholine in eight AD patients with AA (AD+) and eight AD patients without AA (AD-) and studied bronchial and cutaneous responses after allergen inhalation challenge. METHODS: All patients were treated in hospital for their eczema with tar ointment (pix liquida) and orally administered antihistamines (mean hospital stay 37 days). After clearing of the skin lesions allergen inhalation challenge was performed. Cutaneous responses were studied by measuring the 'Costa' score before and 24 h after allergen inhalation challenge. RESULTS: The median value of the provocative concentration of methacholine causing a 20% fall (PC20 Mch) in forced expiratory volume in 1 second (FEV1) was significantly higher in the AD- group compared to the AD+ group with median values of 10.70 and 0.60 mg/mL, respectively. These values did not change significantly in both groups during hospital stay. After challenge all AD+ patients showed early and late asthmatic responses whereas only four AD patients showed early asthmatic responses (mean values of the maximal fall in FEV1 during the EAR 37%/16% and in PEF during the LAR 27%/4% for AD+ and AD-patients, respectively). The 'Costa' score increased in both groups (mean score before 19.1/24.4 and after challenge 26.8/26.9 for AD+ and AD- patients, respectively). The increase in the AD+ group was significantly higher compared with the AD- group (P=0.016). CONCLUSION: We conclude that allergen inhalation challenge causes a flare up of the skin lesions in atopic dermatitis patients. This was more prominent in atopic dermatitis patients who already suffered from an IgE-mediated allergic inflammation in the lung.

Adolescent↗
PubMed1997

Bronchial and skin reactivity in asthmatic patients with and without atopic dermatitis.

It is unclear whether the presence and severity of atopic dermatitis (AD) is predictive for the occurrence and severity of early and late asthmatic responses to inhaled allergens. The aim of this study was to compare the bronchial effects of allergen inhalation challenge in allergic asthma (AA) and atopic dermatitis. We therefore studied these responses in: nine patients with mild-to-moderate AA without AD; eight patients with mild-to-moderate AA and mild AD; eight patients with severe AD and mild AA; and eight patients with severe AD without AA. Allergen challenge was performed by inhaling doubling doses until the dose provoking a 20% fall in forced expiratory volume in one second (PC20) was reached. The late asthmatic reaction (LAR) was defined as a fall of >20% in peak expiratory flow (PEF) between 3 and 8 h after the challenge. All but four of the patients with severe AD without AA developed an early asthmatic response (EAR). A LAR was seen in all patients with severe AD and mild AA, in four patients with mild AD and mild-to-moderate AA, and in three patients with mild-to-moderate AA without AD. The LAR was most pronounced in patients with a combination of mild AA and severe AD. This could be explained, in part, by a decreased skin sensitivity in these patients, which made the Cockcroft formula for prediction of PC20 allergen less accurate in such patients. We conclude that patients with severe atopic dermatitis and mild asthma are at risk for developing pronounced late asthmatic responses after allergen exposure. This suggests that eosinophils activated in atopic dermatitis also predispose to airway inflammation.

Adolescent↗
PubMed1996

Cloning and characterization of Fc alpha Rb, a novel Fc alpha receptor (CD89) isoform expressed in eosinophils and neutrophils.

The Fc receptor for IgA (Fc alpha R, CD89) is a transmembrane glycoprotein found on monocytes, macrophages, neutrophils, and eosinophils. Here we describe the characterization of a novel isoform of the Fc alpha R cloned from a human eosinophil cDNA library. This clone, Fc alpha Rb, lacks the exon encoding the transmembrane/intracellular region of wild type Fc alpha R, which is replaced by 23 new amino acids. Expression of Fc alpha Rb mRNA could be detected in eosinophils and neutrophils. IIA1.6 murine pro-B cells transfected with Fc alpha Rb cDNA secrete high levels of the protein, but also a substantial amount of Fc alpha Rb is expressed at the cell membrane. Membrane-bound Fc alpha Rb binds IgA-coated beads equally well as wild type Fc alpha R. Surface expression is not affected by phosphatidyl inositol phospholipase C, indicating that glycosyl phosphatidyl inositol-linkage of Fc alpha Rb is not likely. In IIA1.6 cells expressing Fc alpha Rb and FcR gamma, which is necessary for signal transduction by wild type Fc alpha R, no tyrosine phosphorylation or Ca(2+)-mobilization could be observed after receptor cross-linking. These results indicate that Fc alpha Rb is likely to have a different function than wild-type Fc alpha R receptor.

Amino Acid Sequence↗
PubMed1996

STAT3beta, a splice variant of transcription factor STAT3, is a dominant negative regulator of transcription.

The 89-kDa STAT3 protein is a latent transcription factor which is activated in response to cytokines (interleukin (IL)-5 and -6) and growth factors (epidermal growth factor). Binding of IL-5 to its specific receptor activates JAK2 which leads to the tyrosine phosphorylation of STAT3 proteins. Here we report the cloning of a cDNA encoding a variant of the transcription factor STAT3 (named STAT3beta) which was isolated by screening an eosinophil cDNA library. Compared to wild-type STAT3, STAT3beta lacks an internal domain of 50 base pairs located near the C terminus. This splice product is a naturally occurring isoform of STAT3 and encodes a 80-kDa protein. We found by reconstitution of the human IL-5R in COS cells that like STAT3, STAT3beta is phosphorylated on tyrosine and binds to the pIRE from the ICAM-1 promoter after IL-5 stimulation. However, STAT3beta fails to activate a pIRE containing promoter in transient transfection assays. Instead, co-expression of STAT3beta inhibits the transactivation potential of STAT3. These results suggests that STAT3beta functions as a negative regulator of transcription.

Amino Acid Sequence↗
PubMed1996

Platelet-dependent primary hemostasis promotes selectin- and integrin-mediated neutrophil adhesion to damaged endothelium under flow conditions.

Co-localization of blood platelets and granulocytes at sites of hemostasis and inflammation has triggered an intense interest in possible interactions between these cellular processes and induction of vessel wall injury. Leukocyte adhesion to endothelial cells decreases with increasing shear and is dependent on an initial rolling phase mediated by selectins. We hypothesized that flow-dependent platelet adhesion at an injured vessel wall will lead to P-selectin expression by platelets, thus mediating leukocyte co-localization. A perfusion chamber was used in which flowing whole blood induced platelet adhesion to a subendothelial matrix (ECM) of cultured human umbilical vein endothelial cells (HUVEC). We compared neutrophil (polymorphonuclear leukocyte [PMN]) interactions with HUVEC and their ECM with and without adhered platelets. PMNs adhered predominantly to ECM-adhered platelets and not to endothelial cells. ECM alone did not support PMN adhesion under flow conditions. PMN adhesion to unstimulated HUVEC was only substantial at low shear (up to 200 cells/mm2 at shear stress 80 mPa). In marked contrast, PMN adhesion to ECM-adhered platelets was dramatically increased, and adhesion was demonstrated at much higher shear stress (up to 640 mPa). Studies with specific antibodies showed that the platelet-dependent neutrophil adhesion was selectin-mediated. Inhibition of P-selectin caused a marked inhibition of adhesion at high shear stress, whereas the role of leukocyte L-selectin was less pronounced. beta2-Integrin-blocking antibodies inhibited static neutrophil adhesion. fMLP induced L-selectin shedding from leukocytes, resulting in decreased leukocyte adhesion. In conclusion, platelet-dependent hemostasis at the ECM appears to be a powerful intermediate in neutrophil-vessel wall interactions at shear stresses that normally do not allow neutrophil adhesion to intact endothelium.

Antibodies, Monoclonal↗
PubMed1996

Mechanisms involved in eosinophil migration. Platelet-activating factor-induced chemotaxis and interleukin-5-induced chemokinesis are mediated by different signals.

Eosinophils play an important role in the pathogenesis of allergic diseases such as allergic asthma. Eosinophil migration in vitro can be divided into directed migration, or chemotaxis, and random migration, or chemokinesis. Here, we studied intracellular signals involved in eosinophil migration in vitro induced by platelet-activating factor (PAF) and interleukin-5 (IL-5), applying a Boyden chamber assay. Migration induced by PAF (10(-11)-10(-6) M) largely consisted of chemotaxis with some chemokinesis, whereas IL-5 (10(-12)-10(-8) M) induced chemokinesis only. Eosinophils were depleted from intracellular and extracellular Ca2+ to study the role of Ca2+ as a second messenger. Ca2+ depletion did not change PAF-induced chemotaxis, however, IL-5-induced chemokinesis was inhibited. Interestingly, PAF, but not IL-5, induced changes in [Ca2+]i. This rise originated mainly from internal stores. Inhibition of protein kinase A by H-89 and protein kinase C by GF 109203X had no effect on both forms of eosinophil migration. Addition of the protein kinase inhibitor staurosporine significantly inhibited IL-5-induced chemokinesis. Inhibition of tyrosine kinases by herbimycin A completely blocked IL-5-induced chemokinesis. PAF and IL-5-induced actin polymerization was studied to compare migratory responses with a migration-associated intracellular response. Ca2+ depletion significantly enhanced PAF-induced (10(-8) M) actin polymerization, whereas IL-5-induced actin polymerization was not influenced. Addition of staurosporine led to an increase in F-actin. Subsequent addition of PAF or IL-5 resulted in an additive increase in F-actin content. In summary, both forms of eosinophil migration are protein kinase A and protein kinase C independent. In contrast to PAF-induced chemotaxis, Il-5-induced chemokinesis was found to be completely Ca2+ and tyrosine kinase dependent.

Actins↗
PubMed1996

Eosinophil cationic protein and immunoglobulin levels in bronchoalveolar lavage fluid obtained from patients with chronic eosinophilic pneumonia.

In chronic eosinophilic pneumonia (CEP), histopathological evidence exists for the degranulation of eosinophils and the release of various toxic proteins. In vitro studies have demonstrated the degranulation of eosinophils in response to aggregated and complexed immunoglobulins. The aims of this study were to investigate: 1) whether the eosinophil cationic protein (ECP) and immunoglobulin (Ig) levels in bronchoalveolar lavage (BAL) fluid from patients with CEP are increased compared to those of healthy controls; 2) and whether a relationship is present between immunoglobulin levels and ECP levels in BAL fluid from patients with CEP. The BAL from 12 patients with CEP was selected, retrospectively, from all BAL analyses performed in our centre between 1986 and 1992. ECP levels were measured using a radioimmunoassay in BAL fluid of patients with CEP and 10 healthy controls. ECP levels and immunoglobulin levels in BAL fluid from patients with CEP were found to be elevated compared to controls (p < 0.001). A relationship was found between IgA levels and ECP levels in BAL fluid from patients with CEP (r = 0.72; p = 0.043). In conclusion, eosinophil cationic protein and immunoglobulin levels were found to be increased in bronchoalveolar lavage fluid from patients with chronic eosinophilic pneumonia. The relationship found between immunoglobulin A levels and eosinophil cationic protein levels may suggest that immunoglobulin A could be involved in the degranulation of eosinophils in chronic eosinophilic pneumonia.

Blood Proteins↗
PubMed1996

Eosinophil priming by cytokines: from cellular signal to in vivo modulation.

Eosinophils play an important role in the effector phase of allergic inflammation. This review will focus on the conversion of the unprimed eosinophil phenotype in the peripheral blood of normal individuals to the primed phenotype found in the peripheral blood and tissues of allergic patients, a phenomenon called priming. Recent data on the signals initiated after cytokine receptor activation on eosinophils will be reviewed.

Calcium↗
PubMed1995

Activation of the STAT3/acute phase response factor transcription factor by interleukin-5.

The receptor for interleukin-5 (IL-5R) is composed of a unique alpha chain (IL-5R alpha) expressed on eosinophils and basophils, associated with a beta c subunit, which is shared by the receptors for IL-3 and granulocyte macrophage-colony stimulating factor. One of the molecular events activated via the IL-5R is the JAK/STAT signaling pathway. Recent reports have shown that IL-5 induces tyrosine phosphorylation of JAK2 followed by the subsequent cell type-specific activation of either STAT1 alpha or STAT5. To identify additional STAT proteins activated by IL-5, we co-transfected the IL-5R with STAT cDNAs in COS cells. We found that IL-5 induces binding of STAT3 to the intercellular adhesion molecule-1 pIRE, and activates STAT3-dependent transcription. Moreover, endogenous STAT3 was tyrosine phosphorylated and activated in human IL-5-stimulated BaF3 cells ectopically expressing the human IL-5R (BaF3/IL5R). These data imply that multiple STAT proteins are involved in gene regulation by IL-5 in a cell type-specific manner. We further demonstrate using C-terminal truncations of the alpha and beta c subunits of the IL-5R that the membrane-proximal STAT activation. Interestingly, a beta c receptor mutant lacking intracellular tyrosine residues is able to mediate STAT3 activation, suggesting that tyrosine phosphorylation of the beta c receptor is not essential for STAT3 activation.

Acute-Phase Reaction↗
PubMed1995

Interleukin-5 signaling in human eosinophils involves JAK2 tyrosine kinase and Stat1 alpha.

Signaling by a wide variety of cytokines, including interferons, interleukins, and growth factors, involves activation of JAK kinases and Stat (Signal transducers and activators of transcription) proteins. At present, not much is known about the molecular mechanisms by which interleukin-5 (IL-5) exerts its diverse biologic effects. Human eosinophils are one of the most important target cells for IL-5 and were used here to study IL-5 signaling in a primary human cell. IL-5 induced rapid and transient tyrosine phosphorylation of JAK2. Moreover, IL-5 induced at least two DNA-binding complexes, using nuclear extracts from normal human eosinophils and the IL-6/interferon-gamma response element of the ICAM-1 promoter (ICAM-1 pIRE) in an electromobility shift assay. From supershift experiments it was concluded that one DNA-binding complex contained Stat1 alpha, probably as a homodimer. Both DNA-binding complexes were inhibited by a phosphotyrosine antibody (4G10), suggesting that tyrosine phosphorylation is required for complex formation. IL-3 and granulocyte-macrophage colony-stimulating factor induced, similar to IL-5, two DNA-binding complexes in human eosinophils, including Stat1 alpha. These data show for the first time that molecular mechanisms of IL-5 signaling in human eosinophils involve members of the JAK kinase family as well as members of the Stat family.

Base Sequence↗
PubMed1995

C5a-induced migration of human monocytes is primed by dexamethasone.

Allergic inflammation in the lung is characteristic of allergic asthma. This inflammatory process is inhibited by treatment with glucocorticoids. One of the cell types involved in the inflammatory process, the monocyte, is found in enhanced numbers in mucosal lung biopsies of asthmatic patients. Little is known about the mechanisms that lead to increased numbers of monocytes in lung tissue. We studied one of the processes involved, chemotaxis, in a modified Boyden Chamber assay. The effect of the antiinflammatory drug dexamethasone was tested on monocyte chemotactic responses to complement fragment C5a. Human monocytes from peripheral blood of normal human volunteers were purified by centrifugal elutriation. The monocytes showed a reproducible chemotactic response toward C5a with an optimum at a concentration of 10(-9) M. After culture of the monocytes overnight, the monocyte responses were clearly impaired. It is interesting that upon culture, dexamethasone increased monocyte chemotaxis in a dose-dependent manner. Analysis of the filters with an image analyzer showed that the effect was not through modulation of a subpopulation of monocytes. This steroid effect was specific and modulated via steroid receptors, because the introduction of RU 38486, a steroid receptor antagonist, completely inhibited the effect of dexamethasone. These findings are a further illustration of the complex mechanisms involved in the orchestration of the inflammatory response in asthma.

Antigens, CD↗
PubMed1995

Negative cross-talk between RelA and the glucocorticoid receptor: a possible mechanism for the antiinflammatory action of glucocorticoids.

Glucocorticoids are efficient antiinflammatory agents, and their effects include transcriptional repression of several cytokines and adhesion molecules. Whereas glucocorticoids down-regulate the expression of genes relevant during inflammation, nuclear factor (NF)-kappa B/Rel proteins function as important positive regulators of these genes. The expression of intercellular adhesion molecule-1 (ICAM-1), which plays an essential role in recruitment and migration of leukocytes to sites of inflammation, is also down-regulated by glucocorticoids. We found that a functional NF-kappa B site in the ICAM-1 promoter, which can be activated by either 12-O-tetradecanoylphorbol-13-acetate or tumor necrosis factor-alpha (TNF alpha), is also the target for glucocorticoids. In this report we present evidence that the ligand-activated glucocorticoid receptor (GR) is able to repress RelA-mediated activation of the ICAM-1 NF-kappa B site. Conversely, transcriptional activation by GR via a glucocorticoid response element is specifically repressed by RelA, but not by other NF-kappa B/Rel family members. Mutational analysis of GR demonstrates that the DNA binding domain and the ligand binding domain are required for the functional repression of NF-kappa B activation. Despite the importance of the DNA binding domain, we found that the transcriptional repression of NF-kappa B, mediated by GR, is not caused by binding of GR to the ICAM-1 NF-kappa B element, but by a physical interaction between the GR and RelA protein. The repressive effect of GR on NF-kappa B-mediated activation was not shared by other steroid/thyroid receptors. Only the progesterone receptor, which belongs to the same subfamily as GR and which possesses high homology with GR, was able to repress NF-kappa B-mediated transcription. These studies highlight a possible molecular mechanism that can explain the antiinflammatory effects of glucocorticoid treatment during inflammation.

Amino Acid Sequence↗