| A cell-impermeable cyclosporine A derivative reduces pathology in a mouse model of allergic lung inflammation. | |
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MedLine Citation:
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PMID: 21057089 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Although the main regulators of leukocyte trafficking are chemokines, another family of chemotactic agents is cyclophilins. Intracellular cyclophilins function as peptidyl-prolyl cis-trans isomerases and are targets of the immunosuppressive drug cyclosporine A (CsA). Cyclophilins can also be secreted in response to stress factors, with elevated levels of extracellular cyclophilins detected in several inflammatory diseases. Extracellular cyclophilins are known to have potent chemotactic properties, suggesting that they might contribute to inflammatory responses by recruiting leukocytes into tissues. The objective of the present study was to determine the impact of blocking cyclophilin activity using a cell-impermeable derivative of CsA to specifically target extracellular pools of cyclophilins. In this study, we show that treatment with this compound in a mouse model of allergic lung inflammation demonstrates up to 80% reduction in inflammation, directly inhibits the recruitment of Ag-specific CD4(+) T cells, and works equally well when delivered at 100-fold lower doses directly to the airways. Our findings suggest that cell-impermeable analogs of CsA can effectively reduce inflammatory responses by targeting leukocyte recruitment mediated by extracellular cyclophilins. Specifically blocking the extracellular functions of cyclophilins may provide an approach for inhibiting the recruitment of one of the principal immune regulators of allergic lung inflammation, Ag-specific CD4(+) T cells, into inflamed airways and lungs. |
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Authors:
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Molly A Balsley; Miroslav Malesevic; Erik J Stemmy; Jason Gigley; Rosalyn A Jurjus; Dallen Herzog; Michael I Bukrinsky; Gunter Fischer; Stephanie L Constant |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-11-05 |
Journal Detail:
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Title: Journal of immunology (Baltimore, Md. : 1950) Volume: 185 ISSN: 1550-6606 ISO Abbreviation: J. Immunol. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-12-03 Completed Date: 2011-01-04 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2985117R Medline TA: J Immunol Country: United States |
Other Details:
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Languages: eng Pagination: 7663-70 Citation Subset: AIM; IM |
Affiliation:
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Department of Microbiology, Immunology, and Tropical Medicine, The George Washington University Medical Center, Washington, DC 20037, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antigens / immunology Asthma / drug therapy*, immunology*, pathology CD4-Positive T-Lymphocytes / immunology*, pathology Cyclophilins / immunology* Cyclosporins / pharmacology* Disease Models, Animal Immunosuppressive Agents / pharmacology* Inflammation / drug therapy, immunology, pathology Lung / immunology, pathology Mice Mice, Inbred BALB C |
| Grant Support | |
ID/Acronym/Agency:
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R01-AI67254/AI/NIAID NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antigens; 0/Cyclosporins; 0/Immunosuppressive Agents; EC 5.2.1.-/Cyclophilins |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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