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Zn2+-induced NF-kappa B-dependent transcriptional activity involves site-specific p65/RelA phosphorylation

机译：Zn2 +诱导的NF-κB依赖性转录活性涉及位点特异性p65 / RelA磷酸化

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摘要

Zinc is an essential micronutrient, but is proinflammatory when inhaled into the lung. While it is recognized that zinc exposure of airway epithelial cells activates the transcription factor NF-kappa B and increases the expression of inflammatory cytokines to mediate this response, the underlying mechanism of NF-kappa B activation remains to be characterized. In this study, we investigated these Zn2+-induced signaling mechanisms in the BEAS-2B human airway epithelial cell line. Fifty micromolars Zn2+ induced NF-kappa B-dependent transcriptional activity. However, this occurred independently of I kappa B alpha degradation, an essential event in activation of the canonical NF-kappa B pathway, which is induced by physiological stimuli such as TNF alpha and IL-1 beta. We also observed that 50 mu M Zn2+ exposure caused p65/RelA phosphorylation on Ser 276, Ser 529, and Ser 536 in both cytoplasmic and nuclear cell fractions. Mutational analysis pointed to Ser 536 of p65/RelA as the determinant of Zn2+-induced NF-kappa B transactivation in BEAS-2B cells. Pharmacological inhibition of IKK alpha/beta activity reduced both Zn2+-induced p65/RelA phosphorylation at Ser 536 and NF-kappa B-dependent transcriptional activity, suggesting that IKK alpha/beta is necessary for these Zn2+-induced effects. Taken together, these data show that exposure to supraphysiological concentrations of Zn2+ induces NF-kappa B-dependent transcription through an alternate mechanism, suggesting a novel pathway for cellular responses to environmental stress. (c) 2006 Elsevier Inc. All rights reserved.
机译：锌是必不可少的微量营养素，但吸入肺后会发炎。尽管认识到锌暴露于气道上皮细胞会激活转录因子NF-κB并增加炎症细胞因子的表达来介导这种反应，但NF-κB激活的潜在机制尚待确定。在这项研究中，我们调查了BEAS-2B人气道上皮细胞系中这些Zn2 +诱导的信号传导机制。五十微摩尔的Zn 2+诱导NF-κB依赖性转录活性。但是，这独立于IκBα降解而发生，IκBα降解是规范性NF-κB途径激活中的必不可少的事件，这是由诸如TNFα和IL-1β的生理刺激诱导的。我们还观察到50μM Zn2 +暴露导致细胞质和核细胞级分中Ser 276，Ser 529和Ser 536的p65 / RelA磷酸化。突变分析指出，p65 / RelA的Ser 536是BEAS-2B细胞中Zn2 +诱导的NF-κB反式激活的决定因素。 IKK alpha / beta活性的药理抑制作用降低了Zn2 +诱导的Ser 536的p65 / RelA磷酸化和NF-κB依赖性转录活性，提示IKK alpha / beta对于这些Zn2 +诱导的作用是必需的。综上所述，这些数据表明，暴露于超生理浓度的Zn2 +会通过另一种机制诱导NF-κB依赖性转录，这提示了细胞对环境胁迫的反应的新途径。 （c）2006 Elsevier Inc.保留所有权利。

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