Joo Seong Soo, Kim Sung Geun, Choi Sun Eun, Kim Yun-Bae, Park Hee Yong, Seo Seong Jun, Choi Young Wook, Lee Min Won, Lee Do Ik
Research Institute of Veterinary Medicine, Chungbuk National University, Republic of Korea.
Eur J Pharmacol. 2009 Jul 1;614(1-3):98-105. doi: 10.1016/j.ejphar.2009.04.047. Epub 2009 May 3.
The increasing prevalence and severity of atopic dermatitis during recent decades has prompted the development of safe and more highly effective drugs. Although topical corticosteroids have been used for more than 50 years as first line therapy for atopic dermatitis, their potential side effects limits their clinical uses. In light of this, steroid-free topical calcineurin inhibitors were developed and have been used in patients with moderate to severe atopic dermatitis. In the present study, we examined if hirsutenone suppressed the profiles of atopic dermatitis development in vitro via mimicry of calcineurin inhibitor actions in mouse splenocytes and RBL-2H3 mast cells. Our results showed that hirsutenone effectively inhibited T cell activation by blocking dephosphorylation of nuclear factor of activated T cells (NFAT). This inhibition was confirmed by inactivation of mitogen-activated protein kinases (MAPKs), which subsequently inhibited production of cytokine mRNAs (interleukin-2, -4, -5, -13 and interferon-gamma) after T cell receptor stimulation. We also showed that the early T cell activation marker, CD25, was suppressed in the presence of hirsutenone after T cell receptor stimulation with anti-CD3. Moreover, degranulation of mast cells was remarkably suppressed, comparable to that by cyclosporine A. This indicates that hirsutenone may specifically inhibit calcium-activated processes in both T cells and mast cells. Therefore, our results suggest that hirsutenone may be a new topical drug candidate, which probably acts by mimicking calcineurin inhibitor mechanisms.
近几十年来，特应性皮炎的患病率和严重程度不断增加，这促使人们研发更安全、更高效的药物。尽管外用糖皮质激素作为特应性皮炎的一线治疗药物已使用了50多年，但其潜在的副作用限制了其临床应用。鉴于此，无类固醇外用钙调神经磷酸酶抑制剂被研发出来，并已用于中重度特应性皮炎患者。在本研究中，我们通过模拟钙调神经磷酸酶抑制剂对小鼠脾细胞和RBL-2H3肥大细胞的作用，研究了hirsutenone在体外是否能抑制特应性皮炎的发展过程。我们的结果表明，hirsutenone通过阻断活化T细胞核因子（NFAT）的去磷酸化有效抑制T细胞活化。丝裂原活化蛋白激酶（MAPK）的失活证实了这种抑制作用，随后在T细胞受体刺激后抑制了细胞因子mRNA（白细胞介素-2、-4、-5、-13和干扰素-γ）的产生。我们还表明，在用抗CD3刺激T细胞受体后，在hirsutenone存在的情况下，早期T细胞活化标志物CD25受到抑制。此外，肥大细胞的脱颗粒明显受到抑制，与环孢素A的抑制效果相当。这表明hirsutenone可能特异性抑制T细胞和肥大细胞中钙激活的过程。因此，我们的结果表明，hirsutenone可能是一种新的外用药物候选物，其作用可能是通过模拟钙调神经磷酸酶抑制剂的机制。
