Document Detail


A small molecule CRTH2 antagonist inhibits FITC-induced allergic cutaneous inflammation.
MedLine Citation:
PMID:  19066314     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A FITC-induced allergic contact hypersensitivity model was used to investigate the role that the prostaglandin D(2) receptor-chemoattractant receptor-homologous molecule expressed on T(h)2 cells (CRTH2) plays in modulating cutaneous inflammation. Our results show that inhibition of CRTH2, achieved via administration of a potent, small molecule antagonist, Compound A (Cmpd A), effectively blocked edema formation and greatly reduced the inflammatory infiltrate and skin pathology observed in drug vehicle-treated animals. Gene expression analysis revealed that Cmpd A administration down-regulated the transcription of a wide range of pro-inflammatory mediators. This correlated with decreases in cytokine and chemokine protein levels, notably IL-4, IL-1beta, tumor necrosis factor-alpha, transforming growth factor-beta, GRO-alpha, MIP-2 and thymic stromal lymphopoietin (TSLP) in FITC-challenged ears. The administration of an anti-TSLP-neutralizing antibody was only partially effective in lowering the FITC-induced inflammatory infiltrate and cytokine production compared with the CRTH2 antagonist. Taken together, these data suggest that blockade of CRTH2 inhibits multiple pathways leading to cutaneous inflammation in this model. This suggests that CRTH2 antagonism may be a viable route for therapeutic intervention in allergic skin diseases, such as atopic dermatitis.
Authors:
Stefen A Boehme; Karin Franz-Bacon; Edward P Chen; Roman Sásik; L James Sprague; Tai Wei Ly; Gary Hardiman; Kevin B Bacon
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2008-12-09
Journal Detail:
Title:  International immunology     Volume:  21     ISSN:  1460-2377     ISO Abbreviation:  Int. Immunol.     Publication Date:  2009 Jan 
Date Detail:
Created Date:  2008-12-22     Completed Date:  2009-08-31     Revised Date:  2010-09-23    
Medline Journal Info:
Nlm Unique ID:  8916182     Medline TA:  Int Immunol     Country:  England    
Other Details:
Languages:  eng     Pagination:  81-93     Citation Subset:  IM    
Affiliation:
Actimis Pharmaceuticals, Inc., 10835 Road to the Cure, San Diego, CA 92121, USA. sboehme@actimis.com
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Line
Cytokines / immunology
Dermatitis, Allergic Contact / drug therapy*,  immunology
Female
Fluorescein-5-isothiocyanate / adverse effects
Gene Expression / drug effects
Humans
Mice
Mice, Inbred BALB C
Prostaglandin Antagonists / therapeutic use*
Prostaglandin D2 / antagonists & inhibitors
Receptors, Immunologic / antagonists & inhibitors*,  immunology
Receptors, Prostaglandin / antagonists & inhibitors*,  immunology
Th2 Cells / drug effects,  immunology
Grant Support
ID/Acronym/Agency:
1 P30 DK 063491-03/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Cytokines; 0/Prostaglandin Antagonists; 0/Receptors, Immunologic; 0/Receptors, Prostaglandin; 0/prostaglandin D2 receptor; 3326-32-7/Fluorescein-5-isothiocyanate; 41598-07-6/Prostaglandin D2
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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