Association of cathepsin E deficiency with development of atopic dermatitis.
Atopic dermatitis (AD) is a pruritic inflammatory skin diseases associated with a family history of atropy. Here we show that mice lacking the endolysosomal aspartic proteinase cathepsin E spontaneously develop skin lesions similar to those of humans with AD when reared under conventional conditions but not under specific pathogen-free conditions. These mice showed the increase in the ratio of CD4+/CD8+ T cells, the strong polarization of naïve T cells to T helper 2 cells, and the systemic accumulation of IL-18 and IL-1beta accompanied by a marked increase in IL-4, IL-5, and IgE. The relative rates of degradation of IL-18 and IL-1beta were significantly lower in cathepsin E-deficient mice than wild-type mice. These results strongly suggest that the development of AD in cathepsin E-deficient mice is initiated by systemic accumulation of IL-18 and IL-1beta, mainly due to their reduced turnover rates. In addition, the reduced expression of cathepsin E was also observed in erythrocytes of both humans with AD and the AD mouse model NC/Nga. Cathepsin E deficiency might thus be responsible for the induction of AD in humans and mice.
Tsukuba
Takayuki
T
Department of Pharmacology, Graduate School of Dental Science, Kyushu University, Higashi-ku, Fukuoka 812-8582.
Okamoto
Kuniaki
K
Okamoto
Yoshiko
Y
Yanagawa
Michiyo
M
Kohmura
Keiko
K
Yasuda
Yoshiyuki
Y
Uchi
Hiroshi
H
Nakahara
Takeshi
T
Furue
Masutaka
M
Nakayama
Keiko
K
Kadowaki
Tomoko
T
Yamamoto
Kenji
K
Nakayama
Keiichi I
KI
D000818:Animals; D020059:Cathepsin E / Q000096:biosynthesis / Q000097:blood / Q000172:deficiency* / Q000235:genetics; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D003876:Dermatitis, Atopic / Q000201:enzymology* / Q000235:genetics* / Q000276:immunology; D003877:Dermatitis, Contact / Q000097:blood / Q000201:enzymology / Q000235:genetics; D004912:Erythrocytes / Q000201:enzymology; D006241:Haptens / Q000633:toxicity; D006801:Humans; D007073:Immunoglobulin E / Q000096:biosynthesis; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020382:Interleukin-18 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018418:Th2 Cells / Q000201:enzymology / Q000276:immunology
D016207:Cytokines; D006241:Haptens; D007375:Interleukin-1; D020382:Interleukin-18; D007073:Immunoglobulin E; D020059:Cathepsin E