Inhibition of mitogen-activated protein kinase kinase blocks T cell proliferation but does not induce or prevent anergy.
Inhibition of mitogen-activated protein kinase kinase blocks T cell proliferation but does not induce or prevent anergy.
复制标题
DOI：
10.4049/jimmunol.160.9.4175
复制
发表时间：
1998-05
影响因子：
4.4
通讯作者：
Dimuthu R. Desilva;Elizabeth A. Jones;M. Favata;Bruce D. Jaffee;R. Magolda;J. Trzăskos;Peggy Scherle
中科院分区：
文献类型：
--
作者：
Dimuthu R. Desilva;Elizabeth A. Jones;M. Favata;Bruce D. Jaffee;R. Magolda;J. Trzăskos;Peggy Scherle
三种丝裂原激活蛋白激酶途径在 T 淋巴细胞激活过程中上调，即细胞外信号调节激酶 (ERK)、Jun NH2 末端激酶和 p38 丝裂原激活蛋白激酶途径。为了检查阻断 ERK 通路对 T 细胞激活的影响，我们使用了抑制剂 U0126，它已被证明可以特异性阻断丝裂原激活蛋白激酶/ERK 激酶 (MEK)（ERK 上游的激酶）。该化合物可抑制响应抗原刺激或交联抗 CD3 加抗 CD28 抗体的 T 细胞增殖，但对 IL-2 诱导的增殖没有影响。 T 细胞增殖的阻断是通过下调 IL-2 mRNA 水平介导的。与阻断抗原刺激后进入细胞周期的治疗不同，通过抑制 MEK 来阻断 Ag 诱导的增殖不会引起无反应性。令人惊讶的是，在没有共刺激的情况下，暴露于 TCR 交联的 T 细胞中无反应性的诱导也不受阻断 MEK 的影响，这与阻断无反应性诱导的环孢菌素 A 治疗不同。这些结果表明，抑制 MEK 可在短期内阻止 T 细胞增殖，但不会对 T 细胞激活或无反应性诱导产生任何长期影响。这些发现可能有助于确定使用丝裂原激活蛋白激酶抑制剂作为免疫抑制剂的可行性。
Three mitogen-activated protein kinase pathways are up-regulated during the activation of T lymphocytes, the extracellular signal-regulated kinase (ERK), Jun NH2-terminal kinase, and p38 mitogen-activated protein kinase pathways. To examine the effects of blocking the ERK pathway on T cell activation, we used the inhibitor U0126, which has been shown to specifically block mitogen-activated protein kinase/ERK kinase (MEK), the kinase upstream of ERK. This compound inhibited T cell proliferation in response to antigenic stimulation or cross-linked anti-CD3 plus anti-CD28 Abs, but had no effect on IL-2-induced proliferation. The block in T cell proliferation was mediated by down-regulating IL-2 mRNA levels. Blocking Ag-induced proliferation by inhibiting MEK did not induce anergy, unlike treatments that block entry into the cell cycle following antigenic stimulation. Surprisingly, induction of anergy in T cells exposed to TCR cross-linking in the absence of costimulation was also not affected by blocking MEK, unlike cyclosporin A treatment that blocks anergy induction. These results suggest that inhibition of MEK prevents T cell proliferation in the short term, but does not cause any long-term effects on either T cell activation or induction of anergy. These findings may help determine the viability of using mitogen-activated protein kinase inhibitors as immune suppressants.