TY - JOUR
T1 - A chalcone derivative suppresses the induction of TSLP in mice and human keratinocytes and attenuates OVA-induced antibody production in mice
AU - Segawa, Ryosuke
AU - Shiraki, Mika
AU - Sudo, Shiori
AU - Shigeeda, Kenichi
AU - Saito, Taiji
AU - Mizuno, Natsumi
AU - Moriya, Takahiro
AU - Yonezawa, Takayuki
AU - Woo, Je Tae
AU - Hiratsuka, Masahiro
AU - Hirasawa, Noriyasu
N1 - Funding Information:
This work was funded in part Grant-in-aid of Challenging Exploratory Research (17K19470) from the Japan Society for the Promotion of Science and the Translational Research Network Program from the Japan Agency for Medical Research and Development.
Funding Information:
This work was funded in part Grant-in-aid of Challenging Exploratory Research ( 17K19470 ) from the Japan Society for the Promotion of Science and the Translational Research Network Program from the Japan Agency for Medical Research and Development .
Publisher Copyright:
© 2019 Elsevier B.V.
PY - 2019/5/15
Y1 - 2019/5/15
N2 - Thymic stromal lymphopoietin (TSLP) is a key epithelial-derived factor that aggravates allergic diseases. Therefore, TSLP inhibitors are candidate compounds for the treatment of allergic diseases. Previously, we reported that KCMH-1, a mouse keratinocyte cell line, constitutively produces TSLP. In this study, we tried to identify inhibitors of TSLP by screening 2169 compounds in KCMH-1 cells and found one such chalcone derivative (code no. 16D10). 16D10 inhibited TSLP expression and TSLP promoter activation in HaCaT cells, a human keratinocyte cell line. Although nuclear factor kappa-B (NF-κB) is a key transcription factor for the induction of TSLP, 16D10 did not inhibit the activation pathway of NF-κB, such as degradation of inhibitor of κB (IκB) and p65 nuclear translocation. 16D10 activated the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor (erythroid-derived 2)-like 2 (Nrf2) system, although this system was not involved in the inhibitory effect of 16D10. 16D10 also inhibited TSLP production in a lipopolysaccharide (LPS)- or ovalbumin (OVA)-induced air-pouch-type inflammation model. Further, repeated 16D10 administration diminished serum immunoglobulin G1 (IgG1) and IgE concentration in an OVA-induced air-pouch-type sensitization model. Taken together, these results indicate that 16D10 is an inhibitor of TSLP production and has an anti-allergic effect. This inhibitory effect is independent of the activation of NF-κB and the Keap1-Nrf2 system. Therefore, 16D10 could be a new type of candidate drug for allergic diseases.
AB - Thymic stromal lymphopoietin (TSLP) is a key epithelial-derived factor that aggravates allergic diseases. Therefore, TSLP inhibitors are candidate compounds for the treatment of allergic diseases. Previously, we reported that KCMH-1, a mouse keratinocyte cell line, constitutively produces TSLP. In this study, we tried to identify inhibitors of TSLP by screening 2169 compounds in KCMH-1 cells and found one such chalcone derivative (code no. 16D10). 16D10 inhibited TSLP expression and TSLP promoter activation in HaCaT cells, a human keratinocyte cell line. Although nuclear factor kappa-B (NF-κB) is a key transcription factor for the induction of TSLP, 16D10 did not inhibit the activation pathway of NF-κB, such as degradation of inhibitor of κB (IκB) and p65 nuclear translocation. 16D10 activated the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor (erythroid-derived 2)-like 2 (Nrf2) system, although this system was not involved in the inhibitory effect of 16D10. 16D10 also inhibited TSLP production in a lipopolysaccharide (LPS)- or ovalbumin (OVA)-induced air-pouch-type inflammation model. Further, repeated 16D10 administration diminished serum immunoglobulin G1 (IgG1) and IgE concentration in an OVA-induced air-pouch-type sensitization model. Taken together, these results indicate that 16D10 is an inhibitor of TSLP production and has an anti-allergic effect. This inhibitory effect is independent of the activation of NF-κB and the Keap1-Nrf2 system. Therefore, 16D10 could be a new type of candidate drug for allergic diseases.
KW - 16D10
KW - Air-pouch-type inflammation
KW - Allergy
KW - Chalcone
KW - Keratinocyte
KW - Thymic stromal lymphopoietin
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U2 - 10.1016/j.ejphar.2019.02.007
DO - 10.1016/j.ejphar.2019.02.007
M3 - Article
C2 - 30753864
AN - SCOPUS:85062073414
VL - 851
SP - 52
EP - 62
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
ER -