A small molecule CRTH2 antagonist inhibits FITC-induced allergic cutaneous inflammation

被引：50

作者：

Boehme, Stefen A. ^{[1
]}

Franz-Bacon, Karin ^{[1
]}

Chen, Edward P. ^{[1
]}

Sasik, Roman ^{[2
,3
]}

Sprague, L. James ^{[2
]}

Ly, Tai Wei ^{[1
]}

Hardiman, Gary ^{[2
,4
]}

Bacon, Kevin B. ^{[1
]}

机构：

[1] Actimis Pharmaceut Inc, San Diego, CA 92121 USA

[2] Univ Calif San Diego, Sch Med, Biomed Genom Microarray Facil, La Jolla, CA 92093 USA

[3] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA

[4] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA

来源：

INTERNATIONAL IMMUNOLOGY | 2009年 / 21卷 / 01期

基金：

美国国家卫生研究院;

关键词：

THYMIC STROMAL LYMPHOPOIETIN; CD4(+) T-CELLS; ATOPIC-DERMATITIS; CUTTING EDGE; MAST-CELLS; EXPRESSION; RECRUITMENT; EOSINOPHIL; INDUCTION; CYTOKINE;

D O I：

10.1093/intimm/dxn127

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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-1 beta, 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.

引用

页码：81 / 93

页数：13

共 35 条

[1] Thymic stfomal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and potently activates mast cells [J].