A Novel Selective Sphingosine Kinase 2 Inhibitor, HWG-35D, Ameliorates the Severity of Imiquimod-Induced Psoriasis Model by Blocking Th17 Differentiation of Naïve CD4 T Lymphocytes
- Authors
- Shin, S.-H.; Kim, H.-Y.; Yoon, H.-S.; Park, W.-J.; Adams, D.R.; Pyne, N.J.; Pyne, S.; Park, J.-W.
- Issue Date
- Nov-2020
- Publisher
- MDPI
- Keywords
- HWG-35D; psoriasis; sphingosine kinase; sphingosine-1-phosphate; T helper type 17 differentiation
- Citation
- International journal of molecular sciences, v.21, no.21
- Journal Title
- International journal of molecular sciences
- Volume
- 21
- Number
- 21
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/79105
- DOI
- 10.3390/ijms21218371
- ISSN
- 1661-6596
- Abstract
- 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 naïve 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.
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