Yasmin Dulkys

Medizinische Hochschule Hannover

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Jörn Elsner

Medizinische Hochschule Hannover

Alexander Kapp

Medizinische Hochschule Hannover

Daniela Kimmig

Medizinische Hochschule Hannover

Sylvia E. Escher

Fraunhofer Institute for Toxicology and Experimental Medicine

Holger Petering

University of Hildesheim

Amanda E. I. Proudfoot

Merck Serono (Switzerland)

Armin Braun

Fraunhofer Institute for Toxicology and Experimental Medicine

Ulf Forssmann

Princeton University

Thomas Buschermöhle

Medizinische Hochschule Hannover

Ines Barg

Medizinische Hochschule Hannover

Cooperative Institutions

Medizinische Hochschule Hannover

Johannes Gutenberg University Mainz

Technical University of Munich

Charité - Universitätsmedizin Berlin

Ludwig-Maximilians-Universität München

Humboldt-Universität zu Berlin

Heidelberg University

University Medical Center of the Johannes Gutenberg University Mainz

Freie Universität Berlin

Philipps University of Marburg

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Down-regulation of CC chemokine receptor 3 protein and mRNA in human eosinophils mediated by IL-3

Journal of Allergy and Clinical Immunology (2002)

Yasmin Dulkys Christof Kluthe Thomas Buschermöhle Ines Barg Sabine Knöl

CC chemokine receptors

CCL13

CCL21

10.1016/s0091-6749(02)81285-4

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Citations (0)

CRIC3, a chemokine receptor inactivator as a novel approach in the treatment of allergic diseases

Journal of Allergy and Clinical Immunology (2003)

J. Elsner Inka Hartung Robert Bader Sylvia E. Escher Nikolaj Spodsberg

10.1016/s0091-6749(03)80999-5

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Donor to donor variation of the chemokine receptor CCR1 on human eosinophils and its prolonged internalization by RANTES*1

Journal of Allergy and Clinical Immunology (2004)

Yasmin Dulkys Sylvia E. Escher J. Elsner

Internalization

CCR1

CC chemokine receptors

CCL13

10.1016/j.jaci.2004.01.037

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Citations (0)

CXC chemokine receptor 4 (CXCR4) on human eosinophils: Studies on constitutive and cytokine-dependent expression

Journal of Allergy and Clinical Immunology (2002)

Jörn Elsner Yasmin Dulkys Thomas Buschermöhle Ines Barg Sabine Knöl

CXC chemokine receptors

CCL21

CCL13

CC chemokine receptors

CXCL2

10.1016/s0091-6749(02)81821-8

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Citations (0)

Differential Activation of CC Chemokine Receptors by AOP-RANTES

Journal of Biological Chemistry (2000)

Jörn Elsner Matthias Mack Hilke Brühl Yasmin Dulkys Daniela Kimmig

RANTES (regulated on activation normal T cell expressed) has been found at elevated levels in biological fluids from patients with a wide range of allergic and autoimmune diseases and is able to attract several subtypes of leukocytes including eosinophils and monocytes into inflamed tissue. Amino-terminal modifications of RANTES produce receptor antagonists which are candidates for blocking this cellular recruitment. Met-RANTES has been shown to modulate inflammation in vivo, while AOP-RANTES is a potent inhibitor of R5 human immunodeficiency virus type 1 (HIV-1) strains and has been shown to down-modulate CCR5 and prevent recycling of the receptor. We have studied the effect of AOP-RANTES in eosinophil activation and have found that it is able to efficiently elicit eosinophil effector functions through CCR3, as measured by the release of reactive oxygen species and calcium mobilization, whereas Met-RANTES is inactive in these assays. AOP-RANTES is found to inhibit CCR3-mediated HIV-1 infection with moderate potency, in contrast to its potent inhibition of CCR5-mediated HIV-1 infection. Furthermore, we have investigated the abilities of these modified proteins to down-modulate CCR1 and CCR3 from the surface of monocytes and eosinophils. We show here that AOP-RANTES is much less effective than RANTES in down-modulation of CCR1. Surprisingly, recycling of CCR1 was minimal after incubation with RANTES while there was complete recycling with AOP-RANTES. In the case of CCR3, no significant difference was found between RANTES and AOP-RANTES in down-modulation and recycling. It therefore appears that trafficking of RANTES receptors follows different patterns, which opens up potential new targets for therapeutic intervention.

CCL13

XCL2

CC chemokine receptors

10.1074/jbc.275.11.7787

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Citations (76)

Natural Porcine Surfactant Augments Airway Inflammation after Allergen Challenge in Patients with Asthma

American Journal of Respiratory and Critical Care Medicine (2003)

Veit J. Erpenbeck Andreas Hagenberg Yasmin Dulkys Jörn Elsner Ralf Bälder

There is increasing evidence for a role of pulmonary surfactant in asthma and allergic inflammation. In murine asthma models, recent studies have demonstrated that surfactant components downregulate the allergic inflammation. Therefore, we tested the hypothesis that in individuals with mild asthma, a natural porcine surfactant preparation (Curosurf) given before segmental allergen challenge can reduce the allergic airway inflammation. Ten patients with asthma and five healthy control subjects were treated in two segments with either Curosurf or vehicle followed by local allergen challenge. Six additional patients with asthma received Curosurf before allergen challenge in one segment as above, but the second segment was instilled with Curosurf without allergen challenge. Unexpectedly, surfactant treatment augmented the eosinophilic inflammation 24 hours after allergen challenge. A direct chemotactic effect of Curosurf was excluded. However, levels of eotaxin and interleukin-5 were increased in bronchoalveolar lavage after Curosurf treatment, whereas IFN-γ-levels and numbers of IFN-γ+ T cells were decreased. Curosurf had no influence on spreading and retention of allergen determined by allergen uptake in mice. These findings demonstrate that treatment with a natural porcine surfactant results in an augmentation of the eosinophilic inflammation after allergen challenge that is more likely due to immunomodulatory effects than to biophysical properties of the surfactant.

10.1164/rccm.200301-104oc

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Citations (52)

Characterization of the CC Chemokine Receptor 3 on Human Keratinocytes

Journal of Investigative Dermatology (2001)

Holger Petering Christoph Kluthe Yasmin Dulkys Peter Kiehl Alexander Kapp

CC chemokine receptors

Characterization

10.1046/j.1523-1747.2001.01302.x

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Citations (27)

IL-3 Induces Down-Regulation of CCR3 Protein and mRNA in Human Eosinophils

The Journal of Immunology (2001)

Yasmin Dulkys Christof Kluthe Thomas Buschermöhle Ines Barg Sabine Knöß

Abstract Cytokines and chemokines are responsible for the attraction and activation of eosinophils in allergic and inflammatory diseases. Whereas cytokines such as IL-3, IL-5, and GM-CSF activate eosinophils via heterodimeric receptors containing a distinct α-chain (binding domain) and a common β-chain (signaling domain), chemokines such as eotaxin activate eosinophils via seven-transmembrane Gi protein-coupled CCRs. Recent studies have demonstrated the importance of CCR3 on human eosinophils that undergo receptor recycling after chemokine activation, but the modulation of this receptor by cytokines has not yet been addressed. In this study, we demonstrate that IL-3 induces a dose- and time-dependent down-regulation of CCR3 from the surface of human eosinophils comparable to the CCR3-specific ligand eotaxin, whereas IL-5, GM-CSF, IL-4, IL-10, IL-13, IFN-γ, and TNF-α had no effect. Maximal down-regulation of CCR3 in response to IL-3 was reached at 24 h. Reduction of CCR3 surface protein in response to IL-3 could be prevented by an anti-IL-3 mAb and was neither due to the release of CC chemokines nor to nonspecific binding of IL-3 to CCR3. Moreover, down-regulation was prevented by phenylarsine oxide, a nonspecific inhibitor of receptor internalization. After 24 h, IL-3-induced decrease of CCR3 surface expression correlated with diminished mRNA expression, suggesting a transcriptional regulation mechanism. Since wortmannin partially inhibited IL-3- but not eotaxin-induced CCR3 down-regulation, receptor down-modulation seems to underlie different signaling events. Therefore, these data suggest a novel role for the cytokine IL-3 in the activation process of eosinophils and its predominant chemokine receptor CCR3.

CCR3

Internalization

10.4049/jimmunol.167.6.3443

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Citations (49)

n-Nonanoyl-CC Chemokine Ligand 14, a Potent CC Chemokine Ligand 14 Analogue That Prevents the Recruitment of Eosinophils in Allergic Airway Inflammation

The Journal of Immunology (2004)

Ulf Forssmann Inka Hartung Ralf Bälder Barbara Fuchs Sylvia E. Escher

Abstract CCR3 is responsible for tissue infiltration of eosinophils, basophils, mast cells, and Th2 cells, particularly in allergic diseases. In this context, CCR3 has emerged as a target for the treatment of allergic asthma. It is well known that the N-terminal domain of chemokines is crucial for receptor binding and, in particular, its activation. Based on this background, we investigated a number of N-terminally truncated or modified peptides derived from the chemokine CCL14/hemofiltrate CC chemokine-1 for their ability to modulate the activity of CCR3. Among 10 derivatives tested, n-nonanoyl (NNY)-CCL14[10–74] (NNY-CCL14) was the most potent at evoking the release of reactive oxygen species and inducing chemotaxis of human eosinophils. In contrast, NNY-CCL14 has inactivating properties on human eosinophils, because it is able to induce internalization of CCR3 and to desensitize CCR3-mediated intracellular calcium release and chemotaxis. In contrast to naturally occurring CCL11, NNY-CCL14 is resistant to degradation by CD26/dipeptidyl peptidase IV. Because inhibition of chemokine receptors through internalization is a reasonable therapeutic strategy being pursued for HIV infection, we tested a potential inhibitory effect of NNY-CCL14 in two murine models of allergic airway inflammation. In both OVA- and Aspergillus fumigatus-sensitized mice, i.v. treatment with NNY-CCL14 resulted in a significant reduction of eosinophils in the airways. Moreover, airway hyper-responsiveness was shown to be reduced by NNY-CCL14 in the OVA model. It therefore appears that an i.v. administered agonist internalizing and thereby inhibiting CCR3, such as NNY-CCL14, has the potential to alleviate CCR3-mediated diseases.

CCR3

CCL17

CC chemokine receptors

Allergic Inflammation

CCL11

CCL13

CXC chemokine receptors

Internalization

10.4049/jimmunol.173.5.3456

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Citations (37)

The CC chemokine receptor 3 CCR3 is functionally expressed on eosinophils but not on neutrophils

European Journal of Immunology (2000)

Renate Höchstetter Gustav Dobos Daniela Kimmig Yasmin Dulkys Alexander Kapp

The chemokine subclasses differ in their biological activity to stimulate different kinds of effector cells via distinct chemokine receptors. Controversial results about the expression of the CC chemokine receptor CCR3 on the surface of human neutrophils have been described. To find out whether eosinophil contamination might be responsible for these diverse observations, CCR3 expression on highly purified neutrophils and eosinophils was investigated. We enriched neutrophils from a heterogeneous granulocyte population with immunomagnetic beads coated with various anti-CD52 monoclonal antibodies. This procedure was suitable to enrich neutrophils with a purity of up to 99.85%. Reverse transcriptase-PCR revealed that CCR3 mRNA was not expressed by CD52-negative selected neutrophils. In contrast to these cells, CCR3 mRNA could be detected in a heterogeneous granulocyte population and CD16-negative selected eosinophils. In addition, spectrofluorometric measurement of intracellular calcium concentration ([Ca2+]i) demonstrated that CD52-negative selected neutrophils did not show a transient [Ca2+]i increase following stimulation with the CCR3 ligand eotaxin, whereas the heterogeneous granulocyte population as well as eosinophils did respond. Therefore, previous studies demonstrating the expression of CCR3 on human neutrophils have to be re-evaluated because CCR3 mRNA detection on human neutrophils due to contamination by mRNA from eosinophils could not be excluded.

CCR3

CC chemokine receptors

CD16

Interleukin 8

10.1002/1521-4141(200010)30:10<2759::aid-immu2759>3.0.co;2-a

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Citations (27)