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PO-322 exerts potent immunosuppressive effects in vitro and in vivo by selectively inhibiting SGK1 activity.
In: British Journal of Pharmacology, Jg. 177 (2020-04-01), Heft 7, S. 1666-1676
Online
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Zugriff:
Background and Purpose: Immunosuppressive drugs have shown great promise in treating autoimmune diseases in recent years. A series of novel oxazole derivatives were screened for their immunosuppressive activity. PO-322 [1H-indole-2,3-dione 3-(1,3-benzoxazol-2-ylhydrazone)] was identified as the most effective of these compounds. Here, we have investigated the mechanism(s) underlying the inhibition of T-cell proliferation in vitro by PO-322, as well as its effects on the delayed-type hypersensitivity (DTH) response and imiquimod-induced dermatitis in vivo. Experimental Approach: T-cell proliferation and apoptosis were analysed with flow cytometry. Cell viability was assessed with a CCK-8 assay. Protein kinase activity was assessed by SelectScreen Kinase Profiling Services. The phosphorylation of signal-regulated molecules was measured by Western blot. Cytokine levels were determined by elisa. The effect of PO-322 on DTH and imiquimod-induced dermatitis was evaluated in BALB/c mice. Key Results: PO-322 inhibited human T-cell proliferation with anti-CD3/anti-CD28 mAbs or alloantigen without significant cytotoxicity. Importantly, PO-322 was a selective inhibitor of the serum- and glucocorticoid-regulated kinase 1 (SGK1) and decreased NDRG1 phosphorylation but not p70S6K, STAT5, Akt, or ERK1/2 phosphorylation. Furthermore, PO-322 inhibited IFN-γ, IL-6, and IL-17 expression but not IL-10 expression. Finally, treatment with PO-322 was safe and effective for ameliorating the DTH response and imiquimod-induced dermatitis in mice. Conclusions and Implications: PO-322 exerted immunosuppressive activity in vitro and in vivo by selectively inhibiting SGK1 activity. PO-322 represents a potential lead compound for the design and development of new drugs for the treatment of autoimmune diseases. [ABSTRACT FROM AUTHOR]
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PO-322 exerts potent immunosuppressive effects in vitro and in vivo by selectively inhibiting SGK1 activity.
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Autor/in / Beteiligte Person: | Lai, Yi ; Luo, Xing‐Yan ; Guo, Hui‐Jie ; Wang, Si‐Yu ; Xiong, Jing ; Yang, Shu‐Xia ; Li, Li‐Mei ; Zou, Qiang ; Mo, Chun‐Fen ; Wang, Yan‐Tang ; Liu, Yang ; Luo, Xing-Yan ; Guo, Hui-Jie ; Wang, Si-Yu ; Yang, Shu-Xia ; Li, Li-Mei ; Mo, Chun-Fen ; Wang, Yan-Tang |
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Zeitschrift: | British Journal of Pharmacology, Jg. 177 (2020-04-01), Heft 7, S. 1666-1676 |
Veröffentlichung: | 2020 |
Medientyp: | academicJournal |
ISSN: | 0007-1188 (print) |
DOI: | 10.1111/bph.14926 |
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