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International Immunology Advance Access originally published online on December 9, 2008
International Immunology 2009 21(1):1-17; doi:10.1093/intimm/dxn118
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© The Japanese Society for Immunology. 2008. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Antagonism of CRTH2 ameliorates chronic epicutaneous sensitization-induced inflammation by multiple mechanisms

Stefen A. Boehme1, Edward P. Chen1, Karin Franz-Bacon1, Roman Sásik2,3, L. James Sprague2, Tai Wei Ly1, Gary Hardiman2,4 and Kevin B. Bacon1

1 Actimis Pharmaceuticals, Inc., 10835 Road to the Cure, Suite 200, San Diego, CA 92121, USA
2 Biomedical Genomics Microarray Facility (BIOGEM), School of Medicine
3 Moore’s Cancer Center
4 Department of Medicine, University of California, La Jolla, San Diego, CA, USA

Correspondence to: S. A. Boehme; E-mail: sboehme{at}actimis.com

Prostaglandin D2 (PGD2) and its receptor chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2) have been implicated in the pathogenesis of numerous allergic diseases. We investigated the role of PGD2 and CRTH2 in allergic cutaneous inflammation by using a highly potent and specific antagonist of CRTH2. Administration of this antagonist ameliorated cutaneous inflammation caused by either repeated epicutaneous ovalbumin or FITC sensitization. Gene expression and ELISA analysis revealed that there was reduced pro-inflammatory cytokine mRNA or protein produced. Importantly, the CRTH2 antagonist reduced total IgE, as well as antigen-specific IgE, IgG1 and IgG2a antibody levels. This reduction in antibody production correlated to reduced cytokines produced by splenocytes following in vitro antigen challenge. An examination of skin CD11c+ dendritic cells (DC) showed that in mice treated with the CRTH2 antagonist, there was a decrease in the number of these cells that migrated to the draining lymph nodes in response to FITC application to the skin. Additionally, naive CD4+ T lymphocytes co-cultured with skin-derived DC from CRTH2 antagonist-treated mice showed a reduced ability to produce a number of cytokines compared with DC from vehicle-treated mice. Collectively, these findings suggest that CRTH2 has a pivotal role in mediating the inflammation and the underlying immune response following epicutaneous sensitization.

Keywords: allergy, CRTH2, inflammation, prostaglandin D2, skin

Transmitting editor: K. Inaba

Received 27 June 2008, accepted 25 September 2008.


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