ArticleEuropean journal of pharmacology2014
Internalization of the chemokine receptor CCR4 can be evoked by orthosteric and allosteric receptor antagonists.
Article in European journal of pharmacology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
33 citing papers in PubMed, 50 citations in OpenAlex.
- Type 2 conventional dendritic cells and regulatory T cells form a barrier tissue circuit to control allergic inflammation.bioRxiv : the preprint server for biology · 2026Article
- GPCR Biased Signaling in Cancer.Handbook of experimental pharmacology · 2026Review
- The CCL17/CCL22-CCR4 Axis in Pain Pathogenesis: A Comprehensive Review of Immune-Mediated Mechanisms and Therapeutic Opportunities.Molecular neurobiology · 2025Review
- The chemokines CCL22 and CCL17 are a defining feature of type 2 stimulated human lung macrophages and exhibit different metabolic dependencies.Frontiers in immunology · 2025Article
- Topical application of a CCL22-binding aptamer suppresses contact allergy.Molecular therapy. Nucleic acids · 2024Article
- Interactions between LAMP3+ dendritic cells and T-cell subpopulations promote immune evasion in papillary thyroid carcinoma.Journal for immunotherapy of cancer · 2024Article
- A Narrative Review of the State of the Art of CCR4-Based Therapies in Cutaneous T-Cell Lymphomas: Focus on Mogamulizumab and Future Treatments.Antibodies (Basel, Switzerland) · 2024Review
- CCL22 mutations drive natural killer cell lymphoproliferative disease by deregulating microenvironmental crosstalk.Nature genetics · 2022Article
- CCL17 Aggravates Myocardial Injury by Suppressing Recruitment of Regulatory T Cells.Circulation · 2022Article
- Skin-resident dendritic cells mediate postoperative pain via CCR4 on sensory neurons.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Systematic Assessment of Chemokine Signaling at Chemokine Receptors CCR4, CCR7 and CCR10.International journal of molecular sciences · 2021Article
- Regulatory T Cells Fail to Suppress Fast Homeostatic Proliferation In Vitro.Life (Basel, Switzerland) · 2021Article
- A Cornflower Extract ContainingMediators of inflammation · 2021Article
- A degradatory fate for CCR4 suggests a primary role in Th2 inflammation.Journal of leukocyte biology · 2020Article
- Structural basis of chemokine and receptor interactions: Key regulators of leukocyte recruitment in inflammatory responses.Protein science : a publication of the Protein Society · 2020Review
- Influence of Chemokine N-Terminal Modification on Biased Agonism at the Chemokine Receptor CCR1.International journal of molecular sciences · 2019Article
- The Angiotensin Receptor Blocker Losartan Suppresses Growth of Pulmonary Metastases via AT1R-Independent Inhibition of CCR2 Signaling and Monocyte Recruitment.Journal of immunology (Baltimore, Md. : 1950) · 2019Article
- Allosteric Modulation of Class A GPCRs: Targets, Agents, and Emerging Concepts.Journal of medicinal chemistry · 2019Review
- CCR4 Antagonists Inhibit TACS medicinal chemistry letters · 2018Article
- β-Arrestin-2-Dependent Signaling Promotes CCR4-mediated Chemotaxis of Murine T-Helper Type 2 Cells.American journal of respiratory cell and molecular biology · 2018Article
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
The chemokine receptor CCR4 has at least two natural agonist ligands, MDC (CCL22) and TARC (CCL17) which bind to the same orthosteric site with a similar affinity. Both ligands are known to evoke chemotaxis of CCR4-bearing T cells and also elicit CCR4 receptor internalization. A series of small molecule allosteric antagonists have been described which displace the agonist ligand, and inhibit chemotaxis. The aim of this study was to determine which cellular coupling pathways are involved in internalization, and if antagonists binding to the CCR4 receptor could themselves evoke receptor internalization. CCL22 binding coupled CCR4 efficiently to β-arrestin and stimulated GTPγS binding however CCL17 did not couple to β-arrestin and only partially stimulated GTPγS binding. CCL22 potently induced internalization of almost all cell surface CCR4, while CCL17 showed only weak effects. We describe four small molecule antagonists that were demonstrated to bind to two distinct allosteric sites on the CCR4 receptor, and while both classes inhibited agonist ligand binding and chemotaxis, one of the allosteric sites also evoked receptor internalization. Furthermore, we also characterize an N-terminally truncated version of CCL22 which acts as a competitive antagonist at the orthosteric site, and surprisingly also evokes receptor internalization without demonstrating any agonist activity. Collectively this study demonstrates that orthosteric and allosteric antagonists of the CCR4 receptor are capable of evoking receptor internalization, providing a novel strategy for drug discovery against this class of target.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.