c-jun controls the ability of IL-12 to induce IL-10 production from human memory CD4+ T cells.
c-jun controls the ability of IL-12 to induce IL-10 production from human memory CD4+ T cells.
复制标题
DOI：
10.4049/jimmunol.0901283
复制
发表时间：
2009-10-01
期刊：
影响因子：
--
通讯作者：
Martin M
中科院分区：
文献类型：
--
作者：
Garcia CA;Wang H;Benakanakere MR;Barrett E;Kinane DF;Martin M
IL-12 p70是一种免疫调节细胞因子，已显示其诱导CD 4 + T细胞产生IL-10，但控制该过程的潜在细胞机制知之甚少。在本研究中，我们证明了IL-12 p70通过PI 3 K依赖的信号传导机制诱导人记忆性CD 4 + T细胞产生IL-10。具体而言，在IL-12 p70存在下刺激人记忆CD 4 + T细胞导致PI 3 K活性增加以及下游组成型活性丝氨酸/苏氨酸激酶、糖原合成酶激酶-3 β（GSK 3 β）的随后磷酸化和失活。PI 3 K的抑制阻止了IL-12 p70对GSK 3 β的失活，以及随后IL-12 p70通过记忆性CD 4 + T细胞增加IL-10水平的能力。此外，GSK 3 β组成型活性形式的异位表达消除了IL-12 p70增加TCR刺激的CD 4 + T细胞产生IL-10的能力。相反，直接抑制GSK 3模拟了IL-12 p70对记忆性CD 4 + T细胞产生IL-10的作用。对下游转录因子的分析表明，IL-12 p70抑制GSK 3 β的能力导致c-Jun水平的增加。IL-12 p70抑制GSK 3 β并诱导c-Jun水平的能力是IL-12增加人记忆CD 4 + T细胞产生IL-10所必需的，因为小干扰RNA介导的c-Jun基因沉默废除了这一过程。这些研究鉴定了IL-12诱导人记忆性CD 4 + T细胞产生IL-10的细胞机制。
IL-12p70 is an immunoregulatory cytokine that has been shown to induce IL-10 production from CD4+ T cells, yet the underlying cellular mechanisms controlling this process are poorly understood. In the present study, we demonstrate that IL-12p70 induces IL-10 production from human memory CD4+ T cells via a PI3K-dependent signaling mechanism. Specifically, stimulation of human memory CD4+ T cells in the presence of IL-12p70 lead to increased PI3K activity and the subsequent phosphorylation and inactivation of the downstream constitutively active serine/threonine kinase, glycogen synthase kinase-3β (GSK3β). Inhibition of PI3K prevented the inactivation of GSK3β by IL-12p70, as well as the subsequent ability of IL-12p70 to augment IL-10 levels by memory CD4+ T cells. Moreover, ectopic expression of a constitutively active form of GSK3β abrogated the ability of IL-12p70 to increase IL-10 production by TCR-stimulated CD4+ T cells. In contrast, direct inhibition of GSK3 mimicked the effect of IL-12p70 on IL-10 production by memory CD4+ T cells. Analysis of downstream transcription factors identified that the ability of IL-12p70 to inactivate GSK3β lead to increased levels of c-Jun. The ability of IL-12p70 to inactivate GSK3β and induce c-Jun levels was required for IL-12 to augment IL-10 production by human memory CD4+ T cells, since small interfering RNA-mediated gene silencing of c-Jun abrogated this process. These studies identify the cellular mechanism by which IL-12 induces IL-10 production from human memory CD4+ T cells.
登录
查看更多内容
影响因子：
15.3
作者：
Ohteki, T;Parsons, M;Zakarian, A;Jones, R G;Nguyen, L T;Woodgett, J R;Ohashi, P S
通讯作者：
Ohashi, P S
影响因子：
15.3
作者：
Gerosa, F;Paganin, C;Peritt, D;Paiola, F;Scupoli, MT;AsteAmezaga, M;Frank, I;Trinchieri, G
通讯作者：
Trinchieri, G
影响因子：
4.4
作者：
Martin, M;Schifferle, RE;Michalek, SM
通讯作者：
Michalek, SM
DOI：
10.1073/pnas.88.10.4143
发表时间：
1991-05-01
影响因子：
11.1
作者：
GUBLER, U;CHUA, AO;GATELY, MK
通讯作者：
GATELY, MK
影响因子：
4.8
作者：
Beurel, Eleonore;Jope, Richard S.
通讯作者：
Jope, Richard S.