IL-22 induced cell proliferation is regulated by PI3K/Akt/mTOR signaling cascade
IL-22 induced cell proliferation is regulated by PI3K/Akt/mTOR signaling cascade
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DOI：
10.1016/j.cyto.2012.06.316
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发表时间：
2012-10-01
期刊：
影响因子：
3.8
通讯作者：
Raychaudhuri, Siba P.
中科院分区：
文献类型：
--
作者：
Mitra, Anupam;Raychaudhuri, Smriti Kundu;Raychaudhuri, Siba P.
目的：白细胞介素22（Interleukin 22，IL-22）是近年来发现的一种新的细胞因子，可诱导人角质形成细胞和成纤维细胞样滑膜细胞（fibroblast like synoviocytes，FLS）的显著增殖，在银屑病和类风湿性关节炎（rheumatoid arthritis，RA）等以角质形成细胞过度增殖为特征的自身免疫性疾病的发病机制中起重要作用。PI 3 K/Akt/mTOR信号级联在细胞生长和存活中起着至关重要的作用。方法：分别从健康志愿者整形手术后的皮肤、银屑病关节炎（PsA）和类风湿关节炎（RA）患者的滑膜组织中分离正常人表皮角质形成细胞（NHEK）和FLS。MTT法检测IL-22对NHEK和FLS增殖的影响。结果：IL-22可诱导NHEK和FLS细胞增殖，并可被双激酶（PI 3 K/mTOR）抑制剂NVP-BEZ 235和mTOR特异性抑制剂Rapamycin有效抑制。在NHEK和FLS中，IL-22显著诱导Akt和mTOR的磷酸化，其被雷帕霉素和NVP-BEZ 235有效阻断。结论：IL-22诱导NHEK和FLS增殖依赖于PI 3 K/ Akt/mTOR信号通路。这一新的观察结果提供了开发靶向PI 3 K/Akt/mTOR信号通路的新疗法的范围，所述新疗法在自身免疫性疾病如银屑病和类风湿性关节炎中。爱思唯尔有限公司出版
Objective: Interleukin 22 (IL-22), a relatively new cytokine has been found to induce significant proliferation of human keratinocytes and fibroblast like synoviocytes (FLS) and thus plays an important role in the pathogenesis of autoimmune diseases like psoriasis and rheumatoid arthritis (RA) which are characterized by hyperproliferation of keratinocytes and FLS respectively. PI3K/Akt/mTOR signaling cascade plays crucial role in cell growth and survival. Therefore our objective was to see the regulatory role of PI3K/Akt/mTOR signaling cascade in IL-22 induced proliferation of keratinocytes and FLS.Methods: Normal human epidermal keratinocytes (NHEK) and FLS were isolated from skin of healthy volunteer's undergone plastic surgery and synovial tissue of psoriatic arthritis (PsA) and RA patients respectively. IL-22 induced proliferation of NHEK and FLS was measured by MIT assay. Phosphorylation of Akt/ mTOR was determined by western blot assay and further confirmed by real time polymerase chain reaction (RT-PCR).Results: We observed that IL-22 induced significant proliferation of NHEK and FLS which was effectively inhibited by dual kinase (PI3K/mTOR) inhibitor, NVP-BEZ235 and specific mTOR inhibitor, Rapamycin. In NHEK and FLS, IL-22 significantly induced phosphorylation of Akt and mTOR which was effectively blocked by Rapamycin and NVP-BEZ235. Further we did RT-PCR in NHEK and found that IL-22 significantly upregulated AKT1 and MTOR gene.Conclusion: These results show that IL-22 induced proliferation of NHEK and FLS is dependent on PI3K/ Akt/mTOR signaling pathway. This novel observation provides the scope to develop new therapeutics targeting PI3K/Akt/mTOR signaling pathway in autoimmune diseases like psoriasis and rheumatoid arthritis. Published by Elsevier Ltd.