A novel selective sphingosine kinase 2 inhibitor, hwg-35d, ameliorates the severity of imiquimod-induced psoriasis model by blocking th17 differentiation of naive cd4 t lymphocytes
- 주제(키워드) HWG-35D , Psoriasis , Sphingosine kinase , Sphingosine-1-phosphate , T helper type 17 differentiation
- 등재 SCIE, SCOPUS
- OA유형 Green Published, Green Accepted, gold
- 발행기관 MDPI AG
- 발행년도 2020
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000174840
- 본문언어 영어
- Published As http://dx.doi.org/10.3390/ijms21218371
- PubMed https://pubmed.ncbi.nlm.nih.gov/33171607
초록/요약
Sphingosine kinases (SK) catalyze the phosphorylation of sphingosine to generate sphingosine-1-phosphate. Two isoforms of SK (SK1 and SK2) exist in mammals. Previously, we showed the beneficial effects of SK2 inhibition, using ABC294640, in a psoriasis mouse model. However, ABC294640 also induces the degradation of SK1 and dihydroceramide desaturase 1 (DES1). Considering these additional effects of ABC294640, we re-examined the efficacy of SK2 inhibition in an IMQ-induced psoriasis mouse model using a novel SK2 inhibitor, HWG-35D, which exhibits nM potency and 100-fold selectivity for SK2 over SK1. Topical application of HWG-35D ameliorated IMQ-induced skin lesions and normalized the serum interleukin-17A levels elevated by IMQ. Application of HWG-35D also decreased skin mRNA levels of interleukin-17A, K6 and K16 genes induced by IMQ. Consistent with the previous data using ABC294640, HWG-35D also blocked T helper type 17 differentiation of naive CD4+ T cells with concomitant reduction of SOCS1. Importantly, HWG-35D did not affect SK1 or DES1 expression levels. These results reaffirm an important role of SK2 in the T helper type 17 response and suggest that highly selective and potent SK2 inhibitors such as HWG-35D might be of therapeutic use for the treatment of psoriasis. © 2020, MDPI AG. All rights reserved.
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