Deregulation of Tpl2 and NF-kappaB signaling and induction of macrophage apoptosis by the anti-depressant drug lithium.
Deregulation of Tpl2 and NF-kappaB signaling and induction of macrophage apoptosis by the anti-depressant drug lithium.
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DOI：
10.1016/j.cellsig.2008.12.010
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发表时间：
2009-04
影响因子：
4.8
通讯作者：
Sun SC
中科院分区：
文献类型：
--
作者：
Zhang M;Jin W;Zhou X;Yu J;Lee AJ;Sun SC
锂是一种抗抑郁药，也具有免疫调节功能。锂的抗炎作用被认为涉及转录因子CREB的激活，尽管其潜在机制尚未完全了解。我们在这里显示，在巨噬细胞中，锂刺激Tp 12，一种已知介导细胞外信号调节激酶（ERK）和下游靶CREB活化的MAP激酶（MAP 3 K）。锂通过诱导p105的降解来激活Tp 12，p105是一种NF-κB前体蛋白，其作为Tp 12的生理抑制剂起作用。锂的这种新功能不涉及对充分表征的锂靶点GSK 3 β的抑制，因为其他已知的GSK 3 β抑制剂不诱导pl 05降解或Tp 12活化。锂还通过TLR 4配体LPS促进Tpl 2和ERK的活化。另一方面，巨噬细胞与锂的长时间孵育导致p105的显著损失和LPS刺激的NF-κB活化的抑制。因此，锂既减弱LPS介导的促炎基因诱导，又诱导巨噬细胞凋亡。这些结果为锂的抗炎功能提供了新的见解。
Lithium is an anti-depressant drug that also possesses immunomodulatory functions. The anti-inflammatory effect of lithium is thought to involve activation of the transcription factor CREB, although the underlying mechanism is incompletely understood. We show here that in macrophages lithium stimulates Tpl2, a MAP kinase kinase kinase (MAP3K) known to mediate activation of extracellular signal regulated kinase (ERK) and the downstream target CREB. Lithium activates Tpl2 by inducing degradation of p105, an NF-κB precursor protein that functions as a physiological inhibitor of Tpl2. This novel function of lithium does not involve inhibition of a well-characterized lithium target, GSK3β, since other known GSK3β inhibitors do not induce p105 degradation or Tpl2 activation. Lithium also promotes the activation of Tpl2 and ERK by the TLR4 ligand LPS. On the other hand, prolonged incubation of macrophages with lithium results in dramatic loss of p105 and inhibition of LPS-stimulated NF-κB activation. Consequently, lithium both attenuates LPS-mediated pro-inflammatory gene induction and induces apoptosis in macrophages. These results provide novel insight into the anti-inflammatory function of lithium.
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DOI：
10.4049/jimmunol.181.1.338
发表时间：
2008-07-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
De Sarno P;Axtell RC;Raman C;Roth KA;Alessi DR;Jope RS
通讯作者：
Jope RS
影响因子：
64.8
作者：
Belich, MP;Salmerón, A;Ley, SC
通讯作者：
Ley, SC
影响因子：
16
作者：
Bertrand, Mathieu J. M.;Milutinovic, Snezana;Barker, Philip A.
通讯作者：
Barker, Philip A.
DOI：
10.1016/j.bbamcr.2005.12.010
发表时间：
2006-02-01
影响因子：
5.1
作者：
Babu, GR;Jin, W;Sun, SC
通讯作者：
Sun, SC
影响因子：
11.4
作者：
Eliopoulos, AG;Wang, CC;Tsichlis, PN
通讯作者：
Tsichlis, PN