DC591017，一种磷酸二酯酶4（PDE4）抑制剂，通过调节PKA-CREB信号传导具有强大的抗炎作用,BIOCHEMICAL PHARMACOLOGY

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DC591017，一种磷酸二酯酶4（PDE4）抑制剂，通过调节PKA-CREB信号传导具有强大的抗炎作用
BIOCHEMICAL PHARMACOLOGY ( IF 5.3 ) Pub Date : 2020-07-01 , DOI: 10.1016/j.bcp.2020.113958
Heng Li , Jian Li , Xianglei Zhang , Chunlan Feng , Chen Fan , Xiaoqian Yang , Rui Zhang , Fenghua Zhu , Yu Zhou , Yechun Xu , Hong Liu , Wei Tang

磷酸二酯酶4（PDE4）通过cAMP的水解在免疫细胞和角质形成细胞中起着至关重要的细胞内酶的作用。在多种炎症性疾病中，PDE4的抑制被认为是一种有效的治疗策略。这项研究旨在评估PDE4抑制剂DC591017在体外和体内的抗炎作用。将小鼠RAW264.7细胞，BMDM，BMDC和人NHEK与DC591017孵育，然后分析炎症介质，细胞内cAMP和cAMP介导的信号通路。进行了角叉菜胶诱导的小鼠气袋和大鼠爪的急性炎症以及咪喹莫特（IMQ）诱导的牛皮癣样皮肤损伤，以探索DC591017的治疗效果和潜在机制。我们在本文中证明了DC591017通过促进cAMP依赖性PKA-CREB信号传导抑制了巨噬细胞和DC的炎症反应。毛喉素的添加与DC591017具有协同作用，在H89干预或通过siRNA转染抑制PKA表达后，它可以被阻断。在体内，DC591017处理可减轻鼠气袋中白细胞的浸润和炎性细胞因子的分泌，并显着减轻角叉菜胶诱发的大鼠足肿胀。此外，我们还表明，局部使用DC591017软膏可改善IMQ引起的实验性银屑病皮肤损伤，这可通过减少表皮增厚和发炎皮肤的炎性浸润来证明。始终如一 DC591017降低了PDE4亚型的表达，并随后调节了PKA-CREB和NF-κB信号传导。简而言之，我们的研究推出了具有强大抗发炎作用的专利PDE4抑制剂，并为银屑病患者的治疗提供了可靠的证据。

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DC591017, a phosphodiesterase-4 (PDE4) inhibitor with robust anti-inflammation through regulating PKA-CREB signaling

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-κB 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.

更新日期：2020-07-01

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