Xu Rui, Feng Shi, Ao Zhou, Chen Yingxiang, Su Congping, Feng Xiuling, Fu Qin, Yang Xiaoyan
Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China.
Front Pharmacol. 2022 Jun 20;13:865715. doi: 10.3389/fphar.2022.865715. eCollection 2022.
Psoriasis is a chronic inflammatory disease that affects approximately 1%-5% of the population worldwide. Considering frequent relapse, adverse drug reactions, and large costs of treatment, it is urgent to identify new medications for psoriasis. Keratinocytes play an essential role during psoriasis development, and they express high levels of β-Adrenergic receptor (β-AR), which increases intracellular cAMP levels when activated. Increased level of cAMP is associated with the inhibition of epidermal cell proliferation. In the present study, we observed the effect of salmeterol, a long-acting β-AR agonist, on the proliferation and apoptosis of keratinocytes as well as imiquimod-induced psoriasis-like skin lesions in mice. As phosphodiesterase 4 (PDE4) inhibitors increases intracellular cAMP concentration by inhibiting its inactivation, we further explored the synergetic effect of a PDE4 inhibitor and salmeterol on psoriasis-like skin lesions in mice. Our results indicated that salmeterol effectively inhibited the proliferation of HaCaT cells induced by TNF-α and serum, and this effect was accompanied by significantly increased apoptosis and CREB phosphorylation, which were reversed by the PKA inhibitor, H89. Salmeterol ameliorated imiquimod-induced psoriasis-like skin lesions in mice, but salmeterol combined with a PDE4 inhibitor had no synergetic effect in improving skin lesions in mice. Of note, the synergistic effects of anti-proliferation and induction of apoptosis in HaCaT cells appeared by inhibiting ERK signaling. In summary, salmeterol, a long-acting β-AR agonist, alleviates the severity of psoriasis inhibiting the proliferation and promoting apoptosis of keratinocytes, partially by activating the cAMP/PKA signaling pathway.
银屑病是一种慢性炎症性疾病，影响着全球约1%-5%的人口。鉴于其频繁复发、药物不良反应以及高昂的治疗成本，迫切需要找到治疗银屑病的新药物。角质形成细胞在银屑病的发展过程中起着至关重要的作用，它们高水平表达β-肾上腺素能受体（β-AR），该受体激活时会增加细胞内cAMP水平。cAMP水平升高与表皮细胞增殖的抑制有关。在本研究中，我们观察了长效β-AR激动剂沙美特罗对角质形成细胞增殖和凋亡的影响，以及对咪喹莫特诱导的小鼠银屑病样皮肤损伤的影响。由于磷酸二酯酶4（PDE4）抑制剂通过抑制cAMP失活来增加细胞内cAMP浓度，我们进一步探究了PDE4抑制剂与沙美特罗对小鼠银屑病样皮肤损伤的协同作用。我们的结果表明，沙美特罗有效抑制了TNF-α和血清诱导的HaCaT细胞增殖，且这一作用伴随着凋亡显著增加和CREB磷酸化，而PKA抑制剂H89可逆转这些变化。沙美特罗改善了咪喹莫特诱导的小鼠银屑病样皮肤损伤，但沙美特罗与PDE4抑制剂联合使用对改善小鼠皮肤损伤并无协同作用。值得注意的是，通过抑制ERK信号传导，在HaCaT细胞中出现了抗增殖和诱导凋亡的协同效应。总之，长效β-AR激动剂沙美特罗通过抑制角质形成细胞增殖和促进其凋亡，部分通过激活cAMP/PKA信号通路，减轻了银屑病的严重程度。
