期刊
EUROPEAN JOURNAL OF PHARMACOLOGY
卷 851, 期 -, 页码 52-62出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2019.02.007
关键词
Allergy; Thymic stromal lymphopoietin; Keratinocyte; 16D10; Chalcone; Air-pouch-type inflammation
资金
- Japan Society for the Promotion of Science [17K19470]
- Translational Research Network Program from the Japan Agency for Medical Research and Development
- Grants-in-Aid for Scientific Research [17K19470] Funding Source: KAKEN
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-kappa B) is a key transcription factor for the induction of TSLP, 16D10 did not inhibit the activation pathway of NF-kappa B, such as degradation of inhibitor of kappa B (I kappa B) 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-kappa B and the Keap1-Nrf2 system. Therefore, 16D10 could be a new type of candidate drug for allergic diseases.
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