新型PDE4抑制剂DC591017通过调控PKA-CREB信号发挥强效抗炎作用

Abstract

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.