Discoidin domain receptor 1 contributes to eosinophil survival in an NF-kappaB-dependent manner in Churg-Strauss syndrome.
Churg-Strauss syndrome (CSS) is a systemic disease that shows marked eosinophilia along with eosinophil infiltration in the tissue. Prolonged eosinophil survival plays an important role in the pathogenesis of CSS; however, its detailed molecular mechanism remains unclear. Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase, and its ligand is collagen. DDR1 was expressed in human leukocytes and fibroblasts, and it plays an important role in leukocyte cytokine production and fibroblast survival in an NF-kappaB-dependent manner. In this study, we examined in vitro and in vivo eosinophil DDR1 expression and its function in CSS patients. The expression level of DDR1 was significantly higher in the eosinophils of CSS patients, and the predominant isoform was DDR1b. Immunohistochemical findings revealed that the tissue-infiltrating eosinophils expressed endogenous DDR1. In CSS patients, DDR1 activation inhibited Fas agonistic antibody-induced apoptosis and up-regulated Fas agonistic antibody-induced cytokine production of eosinophils in an NF-kappaB-dependent manner. Suppression of DDR1 expression in the eosinophils by using RNA interference and addition of the DDR1-blocking protein abolished these effects. We propose that DDR1 contributes to the eosinophil survival in the tissue microenvironment of CSS and that it might be involved in the development of CSS.
Matsuyama
Wataru
W
Division of Respiratory Medicine, Respiratory and Stress Care Center, Kagoshima University Hospital, Kagoshima 890-8520, Japan. vega@xa2.so-net.ne.jp
Mitsuyama
Hideo
H
Ono
Mikiko
M
Shirahama
Yuko
Y
Higashimoto
Ikkou
I
Osame
Mituhiro
M
Arimura
Kimiyoshi
K
D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D002109:Caffeic Acids / Q000494:pharmacology; D002460:Cell Line / Q000378:metabolism; D002470:Cell Survival; D015267:Churg-Strauss Syndrome / Q000503:physiopathology*; D003094:Collagen / Q000378:metabolism / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D000070819:Discoidin Domain Receptor 1; D004804:Eosinophils / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007668:Kidney; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives / Q000494:pharmacology; D020033:Protein Isoforms / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*
D002109:Caffeic Acids; D016207:Cytokines; D016328:NF-kappa B; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D003094:Collagen; C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1; D020794:Receptor Protein-Tyrosine Kinases; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol