Lipopolysaccharide upregulates α7 acetylcholine receptors: stimulation with GTS-21 mitigates growth arrest of macrophages and improves survival in burned mice.
Lipopolysaccharide upregulates α7 acetylcholine receptors: stimulation with GTS-21 mitigates growth arrest of macrophages and improves survival in burned mice.
复制标题
DOI：
10.1097/shk.0b013e31825d628c
复制
发表时间：
2012-08
期刊：
影响因子：
--
通讯作者：
Martyn JA
中科院分区：
文献类型：
--
作者：
Khan MA;Farkhondeh M;Crombie J;Jacobson L;Kaneki M;Martyn JA
烟碱刺激α7乙酰胆碱受体（α7AChRs）可减轻脂多糖（LPS）诱导的巨噬细胞中TNF-α和其他细胞因子的释放。这种作用可被α7AChR拮抗剂α-bungarotoxin （BTX）阻断。我们测试并证实了LPS上调α7AChR的假设，而典型α7AChR拮抗剂维库溴铵和BTX不会阻断GTS-21（一种特异性α7AChR激动剂）对TNF-α释放的作用。通过siRNA敲低α7AChR的表达，GTS-21对TNF-α释放的抑制作用不明显。此外，GTS-21还能减轻lps诱导的J774A.1细胞体外和烧伤后3天小鼠腹膜巨噬细胞体外生长阻滞。此外，GTS-21还能降低小鼠烧伤后的死亡率。结果表明：(1)LPS上调α7AChRs；（ii） GTS-21对细胞因子释放的治疗有益作用是通过α 7achr特异性介导的，即使与原型拮抗剂BTX或临床使用的肌肉尼古丁拮抗剂维库溴铵共同作用也能保持；（iii） GTS-21激活α7AChRs部分逆转lps诱导的增殖阻滞；（iv） GTS-21降低烧伤小鼠的死亡率。GTS-21对烧伤的体内有益作用有待进一步研究。
Nicotinic stimulation of the alpha7 acetylcholine receptors (α7AChRs) mitigates the lipopolysaccharide (LPS)-induced TNF-α and other cytokines release in macrophages. This effect is blocked by α7AChR antagonist, α-bungarotoxin (BTX). We tested and confirmed the hypotheses that LPS up-regulates α7AChRs and the prototypical α7AChR antagonists, vecuronium, and BTX do not block the effects of GTS-21, a specific α7AChR agonist, on TNF-α release. With the knockdown of α7AChR expression by siRNA, GTS-21 effects on inhibition of TNF-α release were not demonstrable. In addition, GTS-21 mitigated the LPS-induced growth arrest of macrophages in vitro in J774A.1 cells and ex vivo in peritoneal macrophages obtained from mice at three days after burn. Moreover, GTS-21 reduced mortality after burn injury in mice. These results indicate that (i) LPS up-regulates α7AChRs; (ii) the therapeutic beneficial effects of GTS-21 on cytokine release are specifically mediated via α7AChRs and are preserved even when co-treated with prototypical antagonist, BTX, or clinically used muscle nicotinic antagonist, vecuronium; (iii) activation of α7AChRs by GTS-21 partially reverses the LPS-induced proliferation arrest and (iv) GTS-21 reduces mortality in mice with burn injury. The in vivo beneficial effects of GTS-21 in burn injury warrant further studies.