HIF-1α Dependent Upregulation of ZIP8, ZIP14, and TRPA1 Modify Intracellular Zn2+ Accumulation in Inflammatory Synoviocytes

Abstract

Intracellular free zinc ([Zn2+]i) is mobilized in neuronal and non-neuronal cells under physiological and/or pathophysiological conditions; therefore, [Zn2+]i is a component of cellular signal transduction in biological systems. Although several transporters and ion channels that carry Zn2+ have been identified, proteins that are involved in Zn2+ supply into cells and their expression are poorly understood, particularly under inflammatory conditions. Here, we show that the expression of Zn2+ transporters ZIP8 and ZIP14 is increased via the activation of hypoxia-induced factor 1α (HIF-1α) in inflammation, leading to [Zn2+]i accumulation, which intrinsically activates transient receptor potential ankyrin 1 (TRPA1) channel and elevates basal [Zn2+]i. 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 Ca2+ oscillations. Assays with fluorescent Zn2+ indicators revealed that the basal [Zn2+]i concentration was significantly higher in TRPA1-expressing HEK cells and inflammatory FLSs. Moreover, TRPA1 activation induced an elevation of [Zn2+]i level in the presence of 1 μM Zn2+ in inflammatory FLSs. Among the 17 out of 24 known Zn2+ transporters, FLSs that were treated with TNF-α and IL-1α exhibited a higher expression of ZIP8 and ZIP14. 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 [Zn2+]i level. Taken together, Zn2+ carrier proteins, TRPA1, ZIP8, and ZIP14, induced under HIF-1α mediated inflammation can synergistically change [Zn2+]i in inflammatory FLSs.

Investigation of the Role of the TRPA1 Ion Channel in Conveying the Effect of Dimethyl Trisulfide on Vascular and Histological Changes in Serum-Transfer Arthritis

“…This coincided with our previous findings in the serum-transfer arthritis model [6]. TRPA1 ion channels are expressed in mesenchymal cells; e.g., in FLS [33]. FLS contribute to K/BxN arthritis by releasing chemokines, cytokines, and matrix metalloproteinases.…”

Aberrant Cerebral Iron Trafficking Co-morbid With Chronic Inflammation: Molecular Mechanisms and Pharmacologic Intervention

“…ZIP8 transcript upregulation and amplified zinc uptake occurs in response to TNFα treatment in primary human lung epithelia and human immortalized lung epithelial cells ( 152 ). Treating synovial fibroblasts with TNFα and IL-1β induced higher zinc concentrations and greater expression of both ZIP8 and ZIP14, which was determined to be dependent on NF-κB signaling downstream of HIF-1α activation ( 153 ). ZIP8 expression is induced by the cytokine, IFN-γ, in intestinal epithelial cells, further propagating the changes in metal homeostasis seen in Crohn's Disease ( 154 ).…”

Correlation of vascular change with TRPV1, TRPV4, and TRPA1 in a rat model of inferior gluteal artery perforator flap

“…In addition, HIF‐1α and TRPA1 protein expression was increased at the postoperative days 1 and 3. The inflammatory stimulus mediated by the NF‐κB signalling, can up‐regulate HIF‐1α expression, 23 which is a key transcription factor in charge of multiple genes expression that promote acclimatisation to hypoxia. HIF‐1α modulates TRPA1 expression through a hypoxia response element‐like motif to regulate cytokine release 24 .…”

“…HIF‐1α modulates TRPA1 expression through a hypoxia response element‐like motif to regulate cytokine release 24 . In brief, inflammatory stimulus can up‐regulate the TRPA1 expression through the NF‐κB signalling and the HIF‐1α 23 . In addition, the amplitude of TRPV1 current increased in hypoxic conditions, the extent of desensitisation decreased, and the phosphorylated TRPV1 protein increased 25 .…”

“…24 In brief, inflammatory stimulus can up-regulate the TRPA1 expression through the NF-κB signalling and the HIF-1α. 23 In addition, the amplitude of TRPV1 current increased in hypoxic conditions, the extent of desensitisation decreased, and the phosphorylated TRPV1 protein increased. 25 Thus, HIF-1α might link the inflammatory cytokines to ion channel expression in hypoxic conditions.…”