Inhibition of IKK down-regulates antigen plus IgE-induced TNF production by mast cells:: a role for the IKK-IκB-NF-κB pathway in IgE-dependent mast cell activation
Inhibition of IKK down-regulates antigen plus IgE-induced TNF production by mast cells:: a role for the IKK-IκB-NF-κB pathway in IgE-dependent mast cell activation
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DOI：
10.1189/jlb.0204115
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发表时间：
2005-06-01
影响因子：
5.5
通讯作者：
Lin, TJ
中科院分区：
文献类型：
--
作者：
Peng, YD;Power, MR;Lin, TJ
肥大细胞(MC)是过敏性疾病的主要效应细胞。免疫球蛋白E(IgE)及其高亲和力受体Fc epsilon RI被抗原交联，启动一系列信号事件，导致核因子(NF)-kappaB激活和肿瘤坏死因子(TNF)产生。在这里，我们证明了Kappa B(I Kappa B)激酶(IKK)的抑制作用可以被一种Kappa B(I Kappa B)激酶(IKK)抑制剂或四种单独的化学IKK抑制剂(包括15-脱氧前列腺素J(2)、BMS-345541、SC-514或舒林酸)显著阻断Ig E+三硝基苯基(TNP)诱导的小鼠骨髓MC产生肿瘤坏死因子。此外，IgE+TNP可诱导BMMC中IKKα的快速磷酸化，但不能诱导IKKβ的快速磷酸化。IgE+TNP诱导的IKKα的磷酸化伴随着I kappaBα的磷酸化和降解、随后的核因子kappaB的激活和肿瘤坏死因子的产生。舒林酸抑制IKK使BMMC的IKKα磷酸化、I kappa Bα磷酸化和降解、核因子-kappaB活化和肿瘤坏死因子的产生减少。有趣的是，IgE+TNP刺激还诱导了IKKα和I kappa Bα的显著合成。吡咯烷二硫代氨基甲酸酯(PDTC)抑制NF-kappa B活性可阻断IgE+TNP诱导的I-kappa Bα合成。当使用PDTC时，即使在IgE+TNP刺激后，核因子-kappaB的活性和色素的产生也受到抑制，这表明新合成的ikappa Bα在MC激活中可能起作用。在……里面。此外，蛋白激酶C(PKC)抑制剂Ro 31-8220可抑制IgE+TNP诱导的IKKα和I kappa Bα的磷酸化。综上所述，我们的结果支持IKK-I kappa B-NF-kappa B途径的作用，该途径可能涉及PKC在MC产生依赖于IgE的肿瘤坏死因子中的作用。因此，IKK可能成为MC在变态反应中功能调节的新靶点。
Mast cells (MC) are major effector cells for allergic diseases. Cross-linking of immunoglobulin E (IgE) and its high-affinity receptor, Fc epsilon RI, by antigen initiates a cascade of signaling events leading to nuclear factor (NF)-kappa B activation and tumor necrosis factor (TNF) production. Here, we demonstrated that inhibition of inhibitor of kappa B (I kappa B) kinase (IKK) by a peptide IKK inhibitor or by four individual chemical IKK inhibitors including 15-deoxyprostaglandin J(2), BMS-345541, SC-514, or sulindac significantly blocked IgE + trinitrophenyl (TNP)-induced TNF production by mouse bone marrow-derived MC (BMMC). Moreover, IgE + TNP induced a rapid phosphorylation of IKK alpha but not IKK beta in BMMC. IgE + TNP-induced phosphorylation of IKK alpha was accompanied with phosphorylation and degradation of I kappa B alpha, subsequent NF-kappa B activation, and TNF production. Inhibition of IKK by sulindac decreased IKK alpha phosphorylation, I kappa B alpha phosphorylation and degradation, NF-kappa B activation, and TNF production by BMMC. It is interesting that IgE + TNP stimulation also induced a prominent synthesis of IKK alpha and I kappa B alpha. Inhibition of NF-kappa B activity by pyrrolidine dithiocarbomate (PDTC) blocked IgE + TNP-induced I kappa B alpha synthesis. NF-kappa B activity and TINT production were also inhibited when PDTC was used even after IgE + TNP stimulation, suggesting a potential role for the newly synthesized I kappa B alpha in MC activation. In. addition, IgE + TNP-induced IKK alpha and I kappa B alpha phosphorylation was inhibited by a protein kinase C (PKC) inhibitor Ro 31-8220. Taken together, our results support a role for the IKK-I kappa B-NF-kappa B pathway, which likely involves PKC in IgE-dependent TNF production by MC. Thus, IKK may serve as a new target for the regulation of MC function in allergy.