Antagonism of CRTH2 ameliorates chronic epicutaneous sensitization-induced inflammation by multiple mechanisms.
Prostaglandin D(2) (PGD(2)) and its receptor chemoattractant receptor homologous molecule expressed on T(h)2 cells (CRTH2) have been implicated in the pathogenesis of numerous allergic diseases. We investigated the role of PGD(2) 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.
Boehme
Stefen A
SA
Actimis Pharmaceuticals, Inc., 10835 Road to the Cure, San Diego, CA 92121, USA. sboehme@actimis.com
Chen
Edward P
EP
Franz-Bacon
Karin
K
Sásik
Roman
R
Sprague
L James
LJ
Ly
Tai Wei
TW
Hardiman
Gary
G
Bacon
Kevin B
KB
D000818:Animals; D015703:Antigens, CD / Q000187:drug effects / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000032:analysis* / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D007136:Immunoglobulins / Q000097:blood / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D015230:Prostaglandin D2 / Q000276:immunology / Q000378:metabolism; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015854:Up-Regulation
D015703:Antigens, CD; D016207:Cytokines; D007136:Immunoglobulins; D011448:Prostaglandin Antagonists; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D010047:Ovalbumin; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor