DC591017, a phosphodiesterase-4 (PDE4) inhibitor with robust anti-inflammation through regulating PKA-CREB signaling | |
Li, Heng1,2; Li, Jian3; Zhang, Xianglei1,4; Feng, Chunlan2; Fan, Chen2; Yang, Xiaoqian2; Zhang, Rui1,3; Zhu, Fenghua2; Zhou, Yu2; Xu, Yechun1,4 | |
刊名 | BIOCHEMICAL PHARMACOLOGY |
2020-07-01 | |
卷号 | 177页码:15 |
关键词 | DC591017 PDE4 Inflammation Macrophages Dendritic cells Psoriasis |
ISSN号 | 0006-2952 |
DOI | 10.1016/j.bcp.2020.113958 |
通讯作者 | Tang, Wei(tangwei@simm.ac.cn) |
英文摘要 | Phosphodiesterase-4 (PDE4) functions as a critical intracellular enzyme in immune cells and keratinocytes through the hydrolysis of cAMP. Inhibition of PDE4 has been considered as an effective therapeutic strategy in multiple inflammatory diseases. This study was intended to assess the anti-inflammatory effects of the PDE4 inhibitor, DC591017, both in vitro and in vivo. Murine RAW264.7 cells, BMDMs, BMDCs, and human NHEKs were incubated with DC591017 and then inflammatory mediators, intracellular cAMP and cAMP-mediated signaling pathways were analyzed. Carrageenan-induced acute inflammation in murine air pouches and rat paws, as well as imiquimod (IMQ)-induced psoriasis-like skin lesions were conducted to explore the therapeutic effects and underlying mechanisms of DC591017. We demonstrated herein that DC591017 suppressed the inflammatory responses of macrophages and DCs through promoting cAMP-dependent PKA-CREB signaling. Addition of forskolin functioned synergistically with DC591017, which could be blocked following H89 intervention or knockdown of PKA expression by siRNA transfection. In vivo, DC591017 treatment alleviated the leukocytes infiltration and secretion of inflammatory cytokines in murine air pouches and significantly attenuated carrageenan-induced paw swelling in rats. Moreover, we also illustrated that topical application of DC591017 ointment ameliorated IMQ-caused experimental psoriatic skin lesions, as evidenced by decreasing epidermal thickening and inflammatory infiltrations to inflamed skins. Consistently, DC591017 decreased expression of PDE4 isoforms and subsequently regulated PKA-CREB and NF-kappa B signaling. In brief, our study brought out a patent PDE4 inhibitor with robust anti-inflammation and provided the credible evidence in the treatment of patients with psoriasis. |
资助项目 | National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09711002-006-011] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences, China[XDA12020231] |
WOS关键词 | INDUCED NEUROINFLAMMATION ; ANTIINFLAMMATORY ACTIVITY ; CELL SUBSETS ; PSORIASIS ; APREMILAST ; IMIQUIMOD ; SKIN ; PATHOGENESIS ; MECHANISMS ; IMMUNITY |
WOS研究方向 | Pharmacology & Pharmacy |
语种 | 英语 |
出版者 | PERGAMON-ELSEVIER SCIENCE LTD |
WOS记录号 | WOS:000541248000033 |
内容类型 | 期刊论文 |
源URL | [http://119.78.100.183/handle/2S10ELR8/291945] |
专题 | 中国科学院上海药物研究所 |
通讯作者 | Tang, Wei |
作者单位 | 1.Univ Chinese Acad Sci, Sch Pharm, Beijing 100049, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Lab Antiinflammat & Immunopharmacol, Shanghai 201203, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 4.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China |
推荐引用方式 GB/T 7714 | Li, Heng,Li, Jian,Zhang, Xianglei,et al. DC591017, a phosphodiesterase-4 (PDE4) inhibitor with robust anti-inflammation through regulating PKA-CREB signaling[J]. BIOCHEMICAL PHARMACOLOGY,2020,177:15. |
APA | Li, Heng.,Li, Jian.,Zhang, Xianglei.,Feng, Chunlan.,Fan, Chen.,...&Tang, Wei.(2020).DC591017, a phosphodiesterase-4 (PDE4) inhibitor with robust anti-inflammation through regulating PKA-CREB signaling.BIOCHEMICAL PHARMACOLOGY,177,15. |
MLA | Li, Heng,et al."DC591017, a phosphodiesterase-4 (PDE4) inhibitor with robust anti-inflammation through regulating PKA-CREB signaling".BIOCHEMICAL PHARMACOLOGY 177(2020):15. |
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