Hypoxia-inducible Factor-1α (HIF1α) Switches on Transient Receptor Potential Ankyrin Repeat 1 (TRPA1) Gene Expression via a Hypoxia Response Element-like Motif to Modulate Cytokine Release

Hatano, Noriyuki; Itoh, Yoshio; Suzuki, Hiroka; Muraki, Yukiko; Hayashi, Hidetoshi; Onozaki, Kikuo; Wood, Ian C.; Beech, David J.; Muraki, Katsuhiko

doi:10.1074/jbc.m112.361139

Cited by 99 publications

(114 citation statements)

References 46 publications

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“…1, C and D). The evoked currents had a similar I-V relationship to that induced by MO, a typical TRPA1 agonist (11). After withdrawal of DPI, these evoked currents were abolished.…”

Section: Resultsmentioning

confidence: 60%

“…TRPA1 expression in HEK cells transfected with TRPA1 plasmid (HEK-TRPA1 cells) was confirmed using the following three assays, as previously described (11,12): TRPA1 mRNA transcript expression, TRPA1 protein expression (see Fig. 5A) and TRPA1 channel function (see Fig.…”

Section: Resultsmentioning

confidence: 98%

“…HEK cells were maintained in Dulbecco's modified minimum essential medium (D-MEM; Sigma, St. Louis, MO) supplemented with 10% heatinactivated fetal calf serum (FCS; JRS Biosciences), penicillin G (100 U/ml), and streptomycin (100 g/ml). Human synoviocytes were purchased from Cell Applications and cultured as described previously in synoviocyte growth medium containing 10% growth supplement, 100 U/ml penicillin G, and 100 g/ml streptomycin (11).…”

Section: Methodsmentioning

confidence: 99%

“…HEK cells were lysed in 50 l lysis buffer [in mM: 50 Tris-HCl (pH 8.0), 150 NaCl, 5 EDTA] including 1% NP-40, 0.5% sodium deoxycholate, 0.1% SDS, and protease inhibitors (11). The cell lysates were incubated on ice for 30 min with vortexing every 5 min and then centrifuged at 20,000 g for 30 min at 4°C.…”

Section: Methodsmentioning

confidence: 99%

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The NADPH oxidase inhibitor diphenyleneiodonium activates the human TRPA1 nociceptor

Suzuki

Hatano

Muraki

et al. 2014

American Journal of Physiology-Cell Physiology

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Transient receptor potential ankyrin 1 (TRPA1) is a Ca 2ϩ -permeable nonselective cation channel expressed in neuronal and nonneuronal cells and plays an important role in acute and inflammatory pain. Here, we show that an NADPH oxidase (NOX) inhibitor, diphenyleneiodonium (DPI), functions as a TRPA1 activator in human embryonic kidney cells expressing human TRPA1 (HEK-TRPA1) and in human fibroblast-like synoviocytes. Application of DPI at 0.03-10 M induced a Ca 2ϩ response in HEK-TRPA1 cells in a concentration-dependent manner. The Ca 2ϩ response was effectively blocked by a selective TRPA1 antagonist, HC-030031 (HC). In contrast, DPI had no effect on HEK cells expressing TRPV1-V4 or TRPM8. Four other NOX inhibitors, apocynin (APO), VAS2870 (VAS), plumbagin, and 2-acetylphenothiazine, also induced a Ca 2ϩ response in HEK-TRPA1 cells, which was inhibited by pretreatment with HC. In the presence of 5 mM glutathione, the Ca 2ϩ response to DPI was effectively reduced. Moreover, mutation of cysteine 621 in TRPA1 substantially inhibited the DPIinduced Ca 2ϩ response, while it did not inhibit the APO-and VASinduced responses. The channel activity was induced by DPI in excised membrane patches with both outside-out and inside-out configurations. Internal application of neomycin significantly inhibited the DPI-induced inward currents. In inflammatory synoviocytes with TRPA1, DPI evoked a Ca 2ϩ response that was sensitive to HC. In mice, intraplantar injection of DPI caused a pain-related response which was inhibited by preadministration with HC. Taken together, our findings demonstrate that DPI and other NOX inhibitors activate human TRPA1 without mediating NOX. calcium channel; transient receptor potential; NADPH oxidase inhibitors TRANSIENT RECEPTOR POTENTIAL ANKYRIN 1 (TRPA1), a Ca 2ϩ -permeable nonselective cation channel widely expressed in neuronal and nonneuronal cells, is activated by noxious cold, mechanical stimulation, irritant chemicals, and some clinical drugs (1,7,12,17,26,28,30,36). Because transgenic mice lacking TRPA1 have suppressed sensitivity to mechanical stimulation, cold stimuli, and TNF␣-induced mechanical hyperalgesia (5,8,20,23,33), the channel has been proposed to be a nociceptor mediating acute and inflammatory pain (3,23,33). Mutagenesis studies have revealed that the cysteine residues 414, 421, and 621 of human TRPA1 are targeted by physiological and nonphysiological electrophilic compounds that activate the channel (14, 26). In contrast, nonelectrophilic compounds, such as ⌬9-tetrahydrocannabinol, nicotine, and menthol, activate TRPA1 via unknown mechanisms (17,18,38). Because numerous structurally unrelated compounds stimulate TRPA1, greater attention should be given to whether common clinical drugs and experimental pharmacological agents activate the channel.The NADPH oxidases (NOXs), a family of transmembrane proteins comprising seven members (NOX1-NOX5, DUOX1, and DUOX2), function as transmembrane electron transporters that use cytosolic NADPH as electron donor and oxygen as electron a...

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“…1, C and D). The evoked currents had a similar I-V relationship to that induced by MO, a typical TRPA1 agonist (11). After withdrawal of DPI, these evoked currents were abolished.…”

Section: Resultsmentioning

confidence: 60%

Section: Resultsmentioning

confidence: 98%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

The NADPH oxidase inhibitor diphenyleneiodonium activates the human TRPA1 nociceptor

Suzuki

Hatano

Muraki

et al. 2014

American Journal of Physiology-Cell Physiology

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“…To further confirm that the CCL20 gene is regulated directly by hypoxia through a HRE [(A/G)CGTG); refs. [30][31][32], high-scoring HRE-like sequences in the CCL20 gene promoter were identified by bioinformatics analysis. Moreover, a ChIP assay using an anti-HIF-1a showed that the putative HRE in the promoter of the CCL20 gene (AGAAGGCGTGTTGCCACA) was captured (Fig.…”

Section: Hif-1a Induces the Expression Of The Cytokine Ccl20 By Mesenmentioning

confidence: 99%

Hypoxia-Induced Epithelial-to-Mesenchymal Transition in Hepatocellular Carcinoma Induces an Immunosuppressive Tumor Microenvironment to Promote Metastasis

et al. 2016

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Portal vein tumor thrombosis (PVTT) is a significant risk factor for metastasis in hepatocellular carcinoma (HCC) patients and is therefore associated with poor prognosis. The presence of PVTT frequently accompanies substantial hypoxia within the tumor microenvironment, which is suggested to accelerate tumor metastasis, but it is unclear how this occurs. Recent evidence has shown that the hypoxia-inducible factor HIF-1a induces epithelial-to-mesenchymal transition (EMT) in tumor cells to facilitate metastasis. In this study, we investigated whether hypoxia-induced EMT in cancer cells also affects immune cells in the tumor microenvironment to promote immunosuppression. We found that hypoxia-induced EMT increased the expression of the CCL20 cytokine in hepatoma cells. Furthermore, coculture of monocyte-derived macrophages with hypoxic hepatoma cells revealed that the expression of indoleamine 2, 3-dioxygenase (IDO) was induced in monocyte-derived macrophages in a CCL20-dependent manner. In turn, these IDOexpressing monocyte-derived macrophages suppressed T-cell proliferation and promoted the expansion of immunosuppressive regulatory T cells. Moreover, high CCL20 expression in HCC specimens was associated with PVTT and poor patient survival. Collectively, our findings suggest that the HIF-1a/ CCL20/IDO axis in hepatocellular carcinoma is important for accelerating tumor metastasis through both the induction of EMT and the establishment of an immunosuppressive tumor microenvironment, warranting further investigation into the therapeutic effects of blocking specific nodes of this signaling network. Cancer Res; 76(4); 818-30. Ó2016 AACR.

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Transient Receptor Potential Ankyrin 1 Receptor Stimulation by Hydrogen Peroxide Is Critical to Trigger Pain During Monosodium Urate–Induced Inflammation in Rodents

Trevisan

Hoffmeister

Rossato

et al. 2013

Arthritis & Rheumatism

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Objective. Gout is a common cause of inflammatory arthritis and is provoked by the accumulation of monosodium urate (MSU) crystals. However, the underlying mechanisms of the pain associated with acute attacks of gout are poorly understood. The aim of this study was to evaluate the role of transient receptor potential ankyrin 1 (TRPA-1) and TRPA-1 stimulants, such as H 2 O 2 , in a rodent model of MSU-induced inflammation.Methods. MSU or H 2 O 2 was injected into the hind paws of rodents or applied in cultured sensory neurons, and the intracellular calcium response was measured in vitro. Inflammatory or nociceptive responses in vivo were evaluated using pharmacologic, genetic, or biochemical tools and methods.Results. TRPA-1 antagonism, TRPA-1 gene deletion, or pretreatment of peptidergic TRP-expressing primary sensory neurons with capsaicin markedly decreased MSU-induced nociception and edema. In addition to these neurogenic effects, MSU increased H 2 O 2 levels in the injected tissue, an effect that was abolished by the H 2 O 2 -detoxifying enzyme catalase. H 2 O 2 , but not MSU, directly stimulated sensory neurons through the activation of TRPA-1. The nociceptive responses evoked by MSU or H 2 O 2 injection were attenuated by the reducing agent dithiothreitol. In addition, MSU injection increased the expression of TRPA-1 and TRP vanilloid channel 1 (TRPV-1) and also enhanced cellular infiltration and interleukin-1␤ levels, and these effects were blocked by TRPA-1 antagonism.Conclusion. Our results suggest that MSU injection increases tissue H 2 O 2 , thereby stimulating TRPA-1 on sensory nerve endings to produce inflammation and nociception. TRPV-1, by a previously unknown mechanism, also contributes to these responses.Gout is the most common cause of painful inflammatory arthritis among men and postmenopausal women. Mainly because of an aging population and lifestyle changes, the incidence and prevalence of gout are steadily increasing (1,2). Poorly controlled gout leads to a limitation of activities and a significant decrease in health-related quality of life (3). Signs and symptoms of gout are caused by soft tissue deposits of monosodium urate (MSU) crystals, which trigger episodes of intense articular and periarticular inflammation and excruciating pain (1,4). However, the underlying mechanism of the inflammatory process in gout that results in sensory symptoms and pain is poorly understood. Accordingly,

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Hypoxia-inducible Factor-1α (HIF1α) Switches on Transient Receptor Potential Ankyrin Repeat 1 (TRPA1) Gene Expression via a Hypoxia Response Element-like Motif to Modulate Cytokine Release

Cited by 99 publications

References 46 publications

The NADPH oxidase inhibitor diphenyleneiodonium activates the human TRPA1 nociceptor

The NADPH oxidase inhibitor diphenyleneiodonium activates the human TRPA1 nociceptor

Hypoxia-Induced Epithelial-to-Mesenchymal Transition in Hepatocellular Carcinoma Induces an Immunosuppressive Tumor Microenvironment to Promote Metastasis

Transient Receptor Potential Ankyrin 1 Receptor Stimulation by Hydrogen Peroxide Is Critical to Trigger Pain During Monosodium Urate–Induced Inflammation in Rodents

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