Inhibition of the nuclear factor κB (NF-κB) pathway by tetracyclic kaurene diterpenes in macrophages -: Specific effects on NF-κB-inducing kinase activity and on the coordinate activation of ERK and p38 MAPK
Inhibition of the nuclear factor κB (NF-κB) pathway by tetracyclic kaurene diterpenes in macrophages -: Specific effects on NF-κB-inducing kinase activity and on the coordinate activation of ERK and p38 MAPK
复制标题
DOI：
10.1074/jbc.m100010200
复制
发表时间：
2001-05-11
影响因子：
4.8
通讯作者：
Boscá, L
中科院分区：
文献类型：
--
作者：
Castrillo, A;de las Heras, B;Boscá, L
大多数萜类化合物的抗炎作用是通过抑制核因子kappaB(NF-kappaB)活性来解释的。Ent-Kaurene二萜类化合物是赤霉素合成的中间产物，能抑制脂多糖刺激的J774巨噬细胞中NO合成酶-2的表达和肿瘤坏死因子-α的释放。这些二萜化合物在体内抑制核因子-kappaB和I-kappaB激酶(IKK)的激活，但在体外不影响核因子-kappaB的功能、I-kappaBα的磷酸化和靶向性以及IKK-2的活性。瞬时表达的核因子-kappaB诱导激酶激活了IKK复合体和核因子-kappaB，这一过程可被角叉烯所抑制，表明抑制该过程是这些二萜类化合物的作用靶点之一。这些结果表明，Kaurenes通过抑制与肿瘤坏死因子受体相关因子相互作用的MAPK激酶超家族成员Nik来损害炎症信号，并通过这些受体介导NF-kappaB的激活。此外，Kaurenes延缓了J774细胞中p38、ERK1和ERK2 MAPKs的磷酸化，而不是JNK的磷酸化。缺乏MAPK和IKK的协同激活可能导致参与这些分子抗炎活性的核因子-kappaB的激活不足。
The anti-inflammatory action of most terpenes has been explained in terms of the inhibition of nuclear factor kappaB (NF-kappaB) activity. Ent-kaurene diterpenes are intermediates of the synthesis of gibberellins and inhibit the expression of NO synthase-2 and the release of tumor necrosis factor-alpha in J774 macrophages challenged with lipopolysaccharide. These diterpenes inhibit NF-kappaB and I kappaB kinase (IKK) activation in vivo but failed to affect in vitro the function of NF-kappaB, the phosphorylation and targeting of I kappaB alpha, and the activity of IKK-2. Transient expression of NF-kappaB-inducing kinase (NIK) activated the IKK complex and NF-kappaB, a process that was inhibited by kaurenes, indicating that the inhibition of NIK was one of the targets of these diterpenes. These results show that kaurenes impair the inflammatory signaling by inhibiting NIK, a member of the MAPK kinase superfamily that interacts with tumor necrosis factor receptor-associated factors, and mediate the activation of NF-kappaB by these receptors. Moreover, kaurenes delayed the phosphorylation of p38, ERK1, and ERK2 MAPKs, but not that of JNK, in response to lipopolysaccharide treatment of J774 cells. The absence of a coordinate activation of MAPK and IKK might contribute to a deficient activation of NF-kappaB that is involved in the anti-inflammatory activity of these molecules.