HIF-1α Dependent Upregulation of ZIP8, ZIP14, and TRPA1 Modify Intracellular Zn<sup>2+</sup> Accumulation in Inflammatory Synoviocytes
Intracellular free zinc ([Zn<sup>2+</sup>]<sub>i</sub>) is mobilized in neuronal and non-neuronal cells under physiological and/or pathophysiological conditions; therefore, [Zn<sup>2+</sup>]<sub>i</sub> is a component of cellular signal transduction in...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-06-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/12/6349 |
| Summary: | Intracellular free zinc ([Zn<sup>2+</sup>]<sub>i</sub>) is mobilized in neuronal and non-neuronal cells under physiological and/or pathophysiological conditions; therefore, [Zn<sup>2+</sup>]<sub>i</sub> is a component of cellular signal transduction in biological systems. Although several transporters and ion channels that carry Zn<sup>2+</sup> have been identified, proteins that are involved in Zn<sup>2+</sup> supply into cells and their expression are poorly understood, particularly under inflammatory conditions. Here, we show that the expression of Zn<sup>2+</sup> transporters ZIP8 and ZIP14 is increased via the activation of hypoxia-induced factor 1α (HIF-1α) in inflammation, leading to [Zn<sup>2+</sup>]<sub>i</sub> accumulation, which intrinsically activates transient receptor potential ankyrin 1 (TRPA1) channel and elevates basal [Zn<sup>2+</sup>]<sub>i</sub>. In human fibroblast-like synoviocytes (FLSs), treatment with inflammatory mediators, such as tumor necrosis factor-α (TNF-α) and interleukin-1α (IL-1α), evoked TRPA1-dependent intrinsic Ca<sup>2+</sup> oscillations. Assays with fluorescent Zn<sup>2+</sup> indicators revealed that the basal [Zn<sup>2+</sup>]<sub>i</sub> concentration was significantly higher in TRPA1-expressing HEK cells and inflammatory FLSs. Moreover, TRPA1 activation induced an elevation of [Zn<sup>2+</sup>]<sub>i</sub> level in the presence of 1 μM Zn<sup>2+</sup> in inflammatory FLSs. Among the 17 out of 24 known Zn<sup>2+</sup> transporters, FLSs that were treated with TNF-α and IL-1α exhibited a higher expression of <i>ZIP8</i> and <i>ZIP14</i>. Their expression levels were augmented by transfection with an active component of nuclear factor-κB P65 and HIF-1α expression vectors, and they could be abolished by pretreatment with the HIF-1α inhibitor echinomycin (Echi). The functional expression of ZIP8 and ZIP14 in HEK cells significantly increased the basal [Zn<sup>2+</sup>]<sub>i</sub> level. Taken together, Zn<sup>2+</sup> carrier proteins, TRPA1, ZIP8, and ZIP14, induced under HIF-1α mediated inflammation can synergistically change [Zn<sup>2+</sup>]<sub>i</sub> in inflammatory FLSs. |
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| ISSN: | 1661-6596 1422-0067 |