IL-33/ST2 axis in inflammation and immunopathology
IL-33/ST2 axis in inflammation and immunopathology
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DOI：
10.1007/s12026-012-8283-9
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发表时间：
2012-04-01
影响因子：
4.4
通讯作者：
Lukic, Miodrag L.
中科院分区：
文献类型：
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作者：
Milovanovic, Marija;Volarevic, Vladislav;Lukic, Miodrag L.
白细胞介素-33（IL-33）是IL-1家族细胞因子的一员，与其质膜受体结合，形成由膜结合的ST 2L和IL-1 R辅助蛋白组成的异源二聚体复合物，诱导NF κ B和MAPK活化。IL-33作为核前体存在，并且当其在细胞损伤后释放时可作为警报蛋白，或者当以内分泌方式起作用时作为NF κ B基因转录的负调节剂。ST 2L在几种免疫细胞上表达：Th 2淋巴细胞、NK、NKT和肥大细胞，以及在髓系细胞上表达：单核细胞、树突细胞和粒细胞。IL-33/ST 2轴可促进Th 1和Th 2免疫应答，这取决于受损组织中活化细胞的类型和微环境以及细胞因子网络。我们先前描述并讨论了IL-33/ST 2轴在1型糖尿病、实验性自身免疫性脑脊髓炎、暴发性肝炎和乳腺癌实验模型中的重要作用。我们发现ST 2缺失增强了T细胞介导的自身免疫性疾病、EAE和I型糖尿病的发展。随着疾病的发展，Th 1/Th 17免疫应答占主导地位，但IL-33的产生也增加，提示IL-33以受体非依赖性方式促进炎性自身反应性T细胞的发展。IL-33/ST 2轴在ConA肝炎中具有保护作用。ST 2缺陷小鼠具有更严重的肝炎，肝脏中的炎性细胞流入更高，并且具有主导的Th 1/Th 17全身反应。用IL-33预处理小鼠通过防止肝细胞凋亡和Th 2扩增来防止Con A诱导的肝损伤。IL-33/ST 2轴的缺失增强NK细胞的细胞毒性、这些细胞中IFN-γ的产生以及IFN-γ、IL-17和TNF-α的全身性产生，这导致肿瘤生长减弱。荷瘤小鼠的IL-33治疗抑制NK细胞的活性、树突状细胞成熟并增强巨噬细胞的交替活化。总之，我们观察到IL-33在T细胞介导的应答中具有减弱的抗炎作用，并且IL-33和ST 2都可以进一步探索作为治疗免疫介导的疾病的潜在治疗靶点。
Interleukin-33 (IL-33), a member of the IL-1 family of cytokines, binds to its plasma membrane receptor, heterodimeric complex consisted of membrane-bound ST2L and IL-1R accessory protein, inducing NFkB and MAPK activation. IL-33 exists as a nuclear precursor and may act as an alarmin, when it is released after cell damage or as negative regulator of NF kappa B gene transcription, when acts in an intracrine manner. ST2L is expressed on several immune cells: Th2 lymphocytes, NK, NKT and mast cells and on cells of myeloid lineage: monocytes, dendritic cells and granulocytes. IL-33/ST2 axis can promote both Th1 and Th2 immune responses depending on the type of activated cell and microenvironment and cytokine network in damaged tissue. We previously described and discuss here the important role of IL-33/ST2 axis in experimental models of type 1 diabetes, experimental autoimmune encephalomyelitis, fulminant hepatitis and breast cancer. We found that ST2 deletion enhance the development of T cell-mediated autoimmune disorders, EAE and diabetes mellitus type I. Disease development was accompanied by dominantly Th1/Th17 immune response but also higher IL-33 production, which suggest that IL-33 in receptor independent manner could promote the development of inflammatory autoreactive T cells. IL-33/ST2 axis has protective role in Con A hepatitis. ST2-deficient mice had more severe hepatitis with higher influx of inflammatory cells in liver and dominant Th1/Th17 systemic response. Pretreatment of mice with IL-33 prevented Con A-induced liver damage through prevention of apoptosis of hepatocytes and Th2 amplification. Deletion of IL-33/ST2 axis enhances cytotoxicity of NK cells, production of IFN-gamma in these cells and systemic production of IFN-gamma, IL-17 and TNF-alpha, which leads to attenuated tumor growth. IL-33 treatment of tumor-bearing mice suppresses activity of NK cells, dendritic cell maturation and enhances alternative activation of macrophages. In conclusion, we observed that IL-33 has attenuated anti-inflammatory effects in T cell-mediated responses and that both IL-33 and ST2 could be further explored as potential therapeutic targets in treatment of immune-mediated diseases.