Curcumin suppresses janus kinase-STAT inflammatory signaling through activation of Src homology 2 domain-containing tyrosine phosphatase 2 in brain microglia
Curcumin suppresses janus kinase-STAT inflammatory signaling through activation of Src homology 2 domain-containing tyrosine phosphatase 2 in brain microglia
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DOI：
10.4049/jimmunol.171.11.6072
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发表时间：
2003-12-01
影响因子：
4.4
通讯作者：
Jou, I
中科院分区：
文献类型：
--
作者：
Kim, HY;Park, EJ;Jou, I
姜黄素被强烈地暗示为抗炎剂，但其作用的确切机制在很大程度上是未知的。在这项研究中，我们发现姜黄素对Janus激酶（JAK）-STAT信号的抑制作用有助于其在大脑中的抗炎活性。在大鼠原代小胶质细胞和小鼠BV 2小胶质细胞中，姜黄素有效地抑制了神经节苷脂、LPS或IFN-γ刺激的环氧合酶-2和诱导型NO合酶（介导炎症过程的重要酶）的诱导。这些抗炎作用似乎至少部分归因于JAK-STAT炎症信号级联的抑制。姜黄素显着抑制磷酸化的STAT 1和3以及JAK 1和2在小胶质细胞激活的神经节苷脂，LPS，或IFN-γ。姜黄素不仅持续抑制NF与IFN-γ激活序列/IFN刺激的调节元件的结合，而且抑制炎症相关基因的表达，包括ICAM-1和单核细胞趋化蛋白1，其启动子含有STAT结合元件。我们进一步表明，激活Src同源2结构域的蛋白酪氨酸磷酸酶（SHP）-2，JAK活性的负调节，可能是姜黄素介导的JAK-STAT信号抑制的机制之一。用姜黄素处理小胶质细胞导致SHP-2的磷酸化和与JAK 1/2的结合增加，这抑制了激活的小胶质细胞中JAK-STAT炎症信号的启动。总之，这些数据表明姜黄素通过激活SHP-2抑制JAK-STAT信号传导，从而减弱脑小胶质细胞的炎症反应。
Curcumin has been strongly implicated as an anti-inflammatory agent, but the precise mechanisms of its action are largely unknown. In this study, we show that the inhibitory action of curcumin on Janus kinase (JAK)-STAT signaling can contribute to its anti-inflammatory activity in the brain. In both rat primary microglia and murine BV2 microglial cells, curcumin effectively suppressed the ganglioside-, LPS-, or IFN-gamma-stimulated induction of cyclooxygenase-2 and inducible NO synthase, important enzymes that mediate inflammatory processes. These anti-inflammatory effects appear to be due, at least in part, to the suppression of the JAK-STAT inflammatory signaling cascade. Curcumin markedly inhibited the phosphorylation of STAT1 and 3 as well as JAK1 and 2 in microglia activated with gangliosides, LPS, or IFN-gamma. Curcumin consistently suppressed not only NF binding to IFN-gamma-activated sequence/IFN-stimulated regulatory element, but also the expression of inflammation-associated genes, including ICAM-1 and monocyte chemoattractant protein 1, whose promoters contain STAT-binding elements. We further show that activation of Src homology 2 domain-containing protein tyrosine phosphatases (SHP)-2, a negative regulator of JAK activity, is likely to be one of the mechanisms underlying the curcumin-mediated inhibition of JAK-STAT signaling. Treatment of microglial cells with curcumin led to an increase in phosphorylation and association with JAK1/2 of SHP-2, which inhibit the initiation of JAK-STAT inflammatory signaling in activated microglia. Taken together, these data suggest curcumin suppresses JAK-STAT signaling via activation of SHP-2, thus attenuating inflammatory response of brain microglial cells.