A small molecule CRTH2 antagonist inhibits FITC-induced allergic cutaneous inflammation.
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.
Boehme
Stefen A
SA
Actimis Pharmaceuticals, Inc., 10835 Road to the Cure, San Diego, CA 92121, USA. sboehme@actimis.com
Franz-Bacon
Karin
K
Chen
Edward P
EP
Sásik
Roman
R
Sprague
L James
LJ
Ly
Tai Wei
TW
Hardiman
Gary
G
Bacon
Kevin B
KB
D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000276:immunology; D017449:Dermatitis, Allergic Contact / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D016650:Fluorescein-5-isothiocyanate / Q000009:adverse effects; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D011448:Prostaglandin Antagonists / Q000627:therapeutic use*; D015230:Prostaglandin D2 / Q000037:antagonists & inhibitors; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000276:immunology; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors* / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology
D016207:Cytokines; D011448:Prostaglandin Antagonists; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D016650:Fluorescein-5-isothiocyanate; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor