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-kappaB and increases the expression of inflammatory cytokines to mediate this response, the underlying mechanism of NF-kappaB 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-kappaB-dependent transcriptional activity. However, this occurred independently of IkappaBalpha degradation, an essential event in activation of the canonical NF-kappaB pathway, which is induced by physiological stimuli such as TNFalpha and IL-1beta. We also observed that 50 microM 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-kappaB transactivation in BEAS-2B cells. Pharmacological inhibition of IKKalpha/beta activity reduced both Zn2+-induced p65/RelA phosphorylation at Ser 536 and NF-kappaB-dependent transcriptional activity, suggesting that IKKalpha/beta is necessary for these Zn2+-induced effects. Taken together, these data show that exposure to supraphysiological concentrations of Zn2+ induces NF-kappaB-dependent transcription through an alternate mechanism, suggesting a novel pathway for cellular responses to environmental stress.
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Article Synopsis
- This study examines how cells process information about cytokine levels via IκB kinases (IKK) to the NF-κB transcription factor, revealing the significance of dynamic signaling in cellular responses.
- Using a microfluidic setup, researchers found that continuous pulse trains of cytokines lead to longer-lasting IKK assemblies, which enhance the retention of NF-κB in the nucleus more effectively than single pulses.
- The findings indicate that variations in cellular responses to cytokines are largely influenced by the behavior of receptor-associated complexes, with simulations accurately predicting NF-κB activity in over 80% of individual cell cases.
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