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饮食干预或药物治疗可重振免疫细胞活力

来源:生物谷 2014-09-03 18:12

2014年9月3日讯 /生物谷BIOON/--来自英国伦敦大学学院、英国癌症研究中心、牛津大学等研究人员完成的两项研究,揭示了营养,代谢和免疫之间的相互作用是如何涉及老化过程,证实了饮食干预或是药物治疗,可以增强我们的免疫力来抵抗疾病,并且有助于使现有的免疫系统治疗更有效。

随着年龄的增长,我们的免疫系统能力下降。老年人患感染和癌症的发病率增加,并且严重程度也会增加。另外,随着年龄增长,接种疫苗效率降低。

由生物技术和生物科学研究理事会(BBSRC)资助,伦敦大学Arne Akbar教授研究小组发现,衰老的免疫系统细胞即T淋巴细胞是由一个名为p38丝裂原活化蛋白激酶(p38 MAPK)的分子控制,其作为一个制动器防止某些细胞功能。

他们发现,这种制动作用,可以通过使用p38蛋白抑制剂逆转,提示使用药物治疗可振兴老化T细胞活力的可能。

发表在Nature Immunology杂志上的研究表明,在低营养水平下,年龄增长或者衰老信号会使细胞内p38 MAPK被激活。研究还表明,对于老化的T淋巴细胞功能,可以通过阻断在参与过程中所涉及的几个分子中的一个进行复原。该研究还表明,老化T淋巴细胞的功能,可以通过阻断此过程中涉及的几个分子之一进行复原。

第二篇论文发表在The Journal of Clinical Investigation杂志上,表明阻断p38蛋白可刺激已经表现出衰老迹象的细胞,使其焕发青春,同时改善线粒体的功能,提高它们的分裂能力。

一个重要的问题是,这类研究结果是否可用于在老化过程中,增强免疫力,许多药物公司已开发p38抑制剂,试图治疗炎性疾病。现在,这些抑制剂的一个新的潜在应用是增强老年人的免疫力。另外,或可采取饮食替代药物治疗增强免疫力。(生物谷Bioon.com)

The kinase p38 activated by the metabolic regulator AMPK and scaffold TAB1 drives the senescence of human T cells

Alessio Lanna,  Sian M Henson,  David Escors  & Arne N Akbar

In T lymphocytes, the mitogen-activated protein kinase (MAPK) p38 regulates pleiotropic functions and is activated by canonical MAPK signaling or the alternative activation pathway downstream of the T cell antigen receptor (TCR). Here we found that senescent human T cells lacked the canonical and alternative pathways for the activation of p38 but spontaneously engaged the metabolic master regulator AMPK to trigger recruitment of p38 to the scaffold protein TAB1, which caused autophosphorylation of p38. Signaling via this pathway inhibited telomerase activity, T cell proliferation and the expression of key components of the TCR signalosome. Our findings identify a previously unrecognized mode for the activation of p38 in T cells driven by intracellular changes such as low-nutrient and DNA-damage signaling (an 'intrasensory' pathway). The proliferative defect of senescent T cells was reversed by blockade of AMPK-TAB1–dependent activation of p38.

p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8+ T cells

Sian M. Henson, et al.

T cell senescence is thought to contribute to immune function decline, but the pathways that mediate senescence in these cells are not clear. Here, we evaluated T cell populations from healthy volunteers and determined that human CD8+ effector memory T cells that reexpress the naive T cell marker CD45RA have many characteristics of cellular senescence, including decreased proliferation, defective mitochondrial function, and elevated levels of both ROS and p38 MAPK. Despite their apparent senescent state, we determined that these cells secreted high levels of both TNF-α and IFN-γ and showed potent cytotoxic activity. We found that the senescent CD45RA-expressing population engaged anaerobic glycolysis to generate energy for effector functions. Furthermore, inhibition of p38 MAPK signaling in senescent CD8+ T cells increased their proliferation, telomerase activity, mitochondrial biogenesis, and fitness; however, the extra energy required for these processes did not arise from increased glucose uptake or oxidative phosphorylation. Instead, p38 MAPK blockade in these senescent cells induced an increase in autophagy through enhanced interactions between p38 interacting protein (p38IP) and autophagy protein 9 (ATG9) in an mTOR-independent manner. Together, our findings describe fundamental metabolic requirements of senescent primary human CD8+ T cells and demonstrate that p38 MAPK blockade reverses senescence via an mTOR-independent pathway.

 

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