Publications by authors named "Sanki Asakawa"

11 Publications

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Lactate released from human fibroblasts enhances Ni elution from Ni plate.

Toxicology 2021 04 14;453:152723. Epub 2021 Feb 14.

Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan. Electronic address:

Elution of Ni ions from medical devices induces inflammation and toxicity. We previously reported that elution of Ni ions from Ni wires induced COX-2 expression and increased lactate production, but whether lactate is involved in the further elution of Ni ions remains unclear. In this study, using KMST-6, a human fibroblast cell line, we examined the molecular mechanisms by which Ni ions increase lactate release and the role of lactate in enhancing the elution of Ni ions. When KMST-6 cells were incubated on a Ni plate or stimulated with NiCl (1 mM), the expression of glucose transporter 1 (GLUT1), hexokinase 2 (HK2), and lactate dehydrogenase A (LDHA), and the release of lactate were enhanced. The NiCl (1 mM)-induced expression of these genes was inhibited by a hypoxia-inducible factor-1α (HIF-1α) inhibitor, PX-478 (10-25 μM). Stimulation of cells with a prolyl hydroxylase domain (PHD) inhibitor, roxadustat, increased the expression of these genes, lactate release, and elution of Ni ions at 10 μM. A monocarboxylate transporter-4 (MCT4) inhibitor, syrosingopine, inhibited lactate release from roxadustat-treated cells and reduced the elution of Ni ions by the cells at 10 μM. Finally, syrosingopine (10 μM) reduced the elution of Ni ions by the cells from the Ni plate. These results suggest that elution of Ni ions from metals promotes the production of lactate via HIF-1α-mediated gene expression and causes further Ni elution. Thus, Ni ions show a positive feedback mechanism of Ni elution, and this step may be potentially targeted to protect against metal elution from metal devices.
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http://dx.doi.org/10.1016/j.tox.2021.152723DOI Listing
April 2021

Suprabasin-null mice retain skin barrier function and show high contact hypersensitivity to nickel upon oral nickel loading.

Sci Rep 2020 09 3;10(1):14559. Epub 2020 Sep 3.

Department of Dermatology, Hamamatsu University School of Medicine, 1-20-1, Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan.

Suprabasin (SBSN) is expressed not only in epidermis but also in epithelial cells of the upper digestive tract where metals such as nickel are absorbed. We have recently shown that SBSN level is decreased in the stratum corneum and serum of atopic dermatitis (AD) patients, especially in intrinsic AD, which is characterized by metal allergy. By using SBSN-null (Sbsn) mice, this study was conducted to investigate the outcome of SBSN deficiency in relation to AD. Sbsn mice exhibited skin barrier dysfunction on embryonic day 16.5, but after birth, their barrier function was not perturbed despite the presence of ultrastructural changes in stratum corneum and keratohyalin granules. Sbsn mice showed a comparable ovalbumin-specific skin immune response to wild type (WT) mice and rather lower contact hypersensitivity (CHS) responses to haptens than did WT mice. The blood nickel level after oral feeding of nickel was significantly higher in Sbsn mice than in WT mice, and CHS to nickel was elevated in Sbsn mice under nickel-loading condition. Our study suggests that the completely SBSN deficient mice retain normal barrier function, but harbor abnormal upper digestive tract epithelium that promotes nickel absorption and high CHS to nickel, sharing the features of intrinsic AD.
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http://dx.doi.org/10.1038/s41598-020-71536-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471289PMC
September 2020

Hypoxia inhibits TNF-α-induced TSLP expression in keratinocytes.

PLoS One 2019 4;14(11):e0224705. Epub 2019 Nov 4.

Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan.

The expression of thymic stromal lymphopoietin (TSLP), a cytokine which greatly contributes to the induction of type I allergy, is upregulated in chronic inflammation such as atopic dermatitis and psoriasis. As hypoxia in the epidermis is important for maintaining skin homeostasis, we examined the regulation of TSLP expression by hypoxic conditions in normal skin epithelial tissues. TNF-α-induced expression of TSLP in human keratinocyte HaCaT and in mouse keratinocyte PAM212 cell lines were inhibited under hypoxic condition (1% O2), although the mRNA expressions of TNF-α, IL-6, IL-8, MCP-1, and VEGF-A were not inhibited. Hypoxia-mimicking conditions, which include NiCl2, CoCl2, and DMOG, an inhibitor of 2-oxoglutarate-dependent enzymes, also selectively inhibited TNF-α-induced TSLP expression. These results suggested that inactivation of prolyl hydroxylase by hypoxia and hypoxia-mimicking conditions is involved in the repression of TNF-α-induced TSLP expression. Interestingly, the inhibition of TSLP production by hypoxic treatment was significantly reversed by treatment with the HIF-2α antagonist but not with the HIF-1α inhibitor. DMOG-induced inhibition of TSLP promoter activity was dependent on the -71 to +185 bp promoter region, suggesting that the binding of HIF-2 to hypoxia response element (HRE) in this region repressed the TSLP expression. These results indicated that hypoxia and hypoxia-mimicking conditions inhibited TSLP expression via HIF-2 and HRE-dependent mechanisms. Therefore, PHD and HIF-2α could be a new strategy for treatment of atopic dermatitis and psoriasis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224705PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827910PMC
April 2020

Zinc ions have a potential to attenuate both Ni ion uptake and Ni ion-induced inflammation.

Sci Rep 2018 02 13;8(1):2911. Epub 2018 Feb 13.

Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, 980-8578, Japan.

Nickel ions (Ni) are eluted from various metallic materials, such as medical devices implanted in human tissues. Previous studies have shown that Ni enters inflammatory cells inducing inflammation. However, the regulation of Ni uptake in cells has not yet been reported in detail. In the present study, we investigated the effects of various divalent cations on Ni uptake and Ni-induced interleukin (IL)-8 production in the human monocytic cell line, THP-1. We demonstrated that ZnCl MnCl, and CoCl inhibited the Ni uptake, while CuCl, FeCl, MgCl, and divalent metal transporter (DMT)-1 inhibitor, Chlorazol Black, did not. Furthermore, ZnCl inhibited Ni-induced IL-8 production, correlating with the inhibition of Ni uptake. These results suggested that Ni uptake occurred through Zn, Mn, and Co-sensitive transporters and that the inhibition of Ni uptake resulted in the inhibition of IL-8 production. Furthermore, using an Ni wire-implanted mouse model, we found that Ni wire-induced expression of mouse macrophage inflammatory protein-2 (MIP-2) and cyclooxygenase-2 (COX-2) mRNA in the skin tissue surrounding the wire were enhanced by low Zn conditions. These results suggested that the physiological concentration of Zn modulates Ni uptake by inflammatory cells, and a Zn deficient state might increase sensitivity to Ni.
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http://dx.doi.org/10.1038/s41598-018-21014-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811449PMC
February 2018

Nickel ions bind to HSP90β and enhance HIF-1α-mediated IL-8 expression.

Toxicology 2018 02 31;395:45-53. Epub 2018 Jan 31.

Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan. Electronic address:

Nickel ions (Ni) eluted from biomedical devices cause inflammation and Ni allergy. Although Ni and Co elicit common effects, Ni induces a generally stronger inflammatory reaction. However, the molecular mechanism by which Ni and Co induce such different responses remains to be elucidated. In the present study, we compared the effects of Ni and Co on the expression of interleukin (IL)-8 in human monocyte THP-1 cells. We report that NiCl but not CoCl induced the expression of IL-8; in contrast, CoCl elicited a higher expression of hypoxia-inducible factor-1α (HIF-1α). The NiCl-induced expression of IL-8 in late phase was blocked by a HIF-1α inhibitor, PX-478, indicating that NiCl targets additional factors responsible for activating HIF-1α. To identify such targets, proteins that bound preferentially to Ni-NTA beads were analyzed by LC/MS/MS. The analysis yielded heat shock protein 90β (HSP90β) as a possible candidate. Furthermore, Ni reduced the interaction of HSP90β with HIF-1α, and instead promoted the interaction between HIF-1α and HIF-1β, as well as the nuclear localization of HIF-1α. Using various deletion variants, we showed that Ni could bind to the linker domain on HSP90β. These results suggest that HSP90β plays important roles in Ni-induced production of IL-8 and could be a potential target for the regulation of Ni-induced inflammation.
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http://dx.doi.org/10.1016/j.tox.2018.01.006DOI Listing
February 2018

LPS priming in early life decreases antigen uptake of dendritic cells via NO production.

Immunobiology 2018 01 9;223(1):25-31. Epub 2017 Oct 9.

Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Japan. Electronic address:

Immunological mechanisms of hygiene hypothesis are expected to develop a novel strategy for allergy prevention. Although a large number of studies has investigated the relation between allergies and infection, little is known about the influence of the exposure to infections on antigen uptake by dendritic cells (DCs). In this study, we examined the effect of lipopolysaccharide (LPS) priming in early life on the antigen uptake ability of DCs by using an original mouse model. LPS priming in juvenile mice decreased the migration of antigen-capturing CD11c cells in the lymph nodes, but not in aged mice. Besides, the bone marrow-derived DCs (BMDCs) from juvenile LPS-primed mice had the poor antigen uptake ability, and constitutively produced NO through the inducible nitric oxide synthase (iNOS). Interestingly, the LPS priming-induced poor antigen uptake of BMDCs was mimicked by the NO donor, and recovered by the iNOS inhibitor. Additionally, LPS priming in juvenile mice prevented the allergic reactions, but not in aged mice. Our results suggested that an exposure to infections in early life prevents allergy through the alteration of the BM cells fate that is to induce the differentiation of BM cells into inhibitory DCs such as NO-producing DCs.
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http://dx.doi.org/10.1016/j.imbio.2017.10.018DOI Listing
January 2018

Induced histamine regulates Ni elution from an implanted Ni wire in mice by downregulating neutrophil migration.

Exp Dermatol 2017 10 3;26(10):868-874. Epub 2017 May 3.

Laboratory of Pharmacotherapy of Life-style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.

Histamine regulates various inflammatory reactions. We have reported that the expression of histidine decarboxylase (HDC) was induced by subcutaneous implantation of nickel (Ni) wire. However, the source and functions of histamine in Ni elution and Ni wire-induced inflammation have not been completely studied. We aimed to elucidate the effects of de novo synthesized histamine on leucocyte infiltration and Ni elution. Implantation of Ni wire induced an increase in the Ni ion content of the surrounding tissues and serum and in the mRNA levels of HDC, a histamine-producing enzyme, macrophage inflammatory protein-2 (MIP-2), a chemoattractant for neutrophils, and monocyte chemoattractant protein-1 (MCP-1), a chemoattractant for monocytes. The Ni wire induced HDC expression even in mast cell-deficient WBB6F1-W/W mice. In HDC knockout (HDC KO) mice, the Ni wire-induced increase in MIP-2 mRNA expression was significantly higher than that in wild-type mice but not MCP-1. MIP-2 expression was enhanced in histamine H2 receptor knockout (H2R KO) mice but not in WBB6F1-W/W mice. Histamine inhibited NiCl -induced MIP-2 mRNA expression in mouse bone marrow-derived macrophages (BMDMs) obtained from wild-type mice; this inhibition was not observed in BMDMs from H2R KO mice. Ni elution increased in HDC KO mice, in which leucocyte infiltration also increased, and was suppressed in mice treated with neutrophil-specific antibody. These results suggest that the Ni wire induced HDC expression in non-mast cells and that, in the chronic phase of inflammation, endogenous histamine reduced Ni elution, probably through regulation of MIP-2 expression and neutrophil migration.
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http://dx.doi.org/10.1111/exd.13315DOI Listing
October 2017

Down-regulation of Na/H exchanger 1 by Toll-like receptor stimulation in macrophages.

Immunobiology 2017 02 11;222(2):176-182. Epub 2016 Oct 11.

Laboratory of Pharmacotherapy of Lifestyle Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan. Electronic address:

The role of Na/H exchanger 1 (NHE1) in various cell types, including inflammatory cells, has been extensively studied. However, regulation of NHE1 protein level in activated inflammatory cells is yet to be characterized. In this study, we investigated whether Toll-like receptor (TLR) ligands can regulate NHE1 protein level in the mouse macrophage-like RAW 264 cell line. We found that lipopolysaccharide (LPS), a TLR4 ligand, lowered NHE1 level and activity in RAW 264 cells and in primary murine macrophages. Other TLR ligands, such as zymosan A and poly(I:C), also displayed reduced NHE1 level. LPS promoted NHE1 ubiquitination and reduced the expression of calcineurin homologous protein 1 (CHP1), a regulator of NHE1 activity and stability. These responses were inhibited by c-Jun N-terminal kinase (JNK) inhibitor SP600125 and dexamethasone. A proteasome inhibitor, but not caspase-3 or lysosomal inhibitors, blocked the LPS-induced NHE1 down-regulation. These results suggested that LPS promotes the degranulation of NHE1 mediated by the ubiquitin-proteasome system and CHP1 downregulation resulting from activation of JNK.
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http://dx.doi.org/10.1016/j.imbio.2016.10.005DOI Listing
February 2017

Involvement of COX-2 in nickel elution from a wire implanted subcutaneously in mice.

Toxicology 2016 07 22;363-364:37-45. Epub 2016 Jul 22.

Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan. Electronic address:

Many types of medical alloys include nickel (Ni), and the elution of Ni ions from these materials causes toxicities and inflammation. We have previously reported that inflammation enhances Ni elution, although the molecular mechanisms underlying this effect remain unclear. In this study, we investigated how inflammatory responses enhanced Ni elution in a wire-implantation mouse model. Subcutaneous implantation of Ni wire induced the expression of cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1) mRNA in the surrounding tissues. Immunostaining analysis showed that cells expressing COX-2 were mainly fibroblast-like cells 8h after implantation of a Ni wire, but were mainly infiltrated leukocytes at 24h. NiCl2 induced the expression of COX-2 mRNA in primary fibroblasts, neutrophils, RAW 264 cells, and THP-1 cells, indicating that Ni ions can induce COX-2 expression in various types of cells. The elution of Ni ions from the implanted Ni wire at 8h was reduced by dexamethasone (Dex), indomethacin (Ind), or celecoxib (Cel) treatment. Ni wire implantation induced an increase in mRNA levels for anaerobic glycolytic pathway components glucose transporter 1 (GLUT1), hexokinase 2 (HK2), lactate dehydrogenase A (LDHA), and monocarboxylate transporter 4 (MCT4); the expression of these genes was also inhibited by Dex, Ind, and Cel. In primary fibroblasts, the expression of these mRNAs and the production of lactate were induced by NiCl2 and further potentiated by PGE2. Furthermore, Ni wire-induced infiltration of inflammatory leukocytes was significantly reduced by Dex, Ind, or Cel. Depletion of neutrophils with a specific antibody caused reduction of both leukocyte infiltration and Ni elution. These results indicate that Ni ions eluted from wire induced COX-2 expression, which further promoted elution of Ni ions by increasing lactate production and leukocyte infiltration. Since COX inhibitors and Dex reduced the elution of Ni ions, these drugs may be useful for prevention of metal-related inflammation and allergy.
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http://dx.doi.org/10.1016/j.tox.2016.07.013DOI Listing
July 2016

Intrinsic atopic dermatitis shows high serum nickel concentration.

Allergol Int 2015 Jul 12;64(3):282-4. Epub 2015 Feb 12.

Department of Dermatology, Hamamatsu University School of Medicine, Shizuoka, Japan.

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http://dx.doi.org/10.1016/j.alit.2015.01.003DOI Listing
July 2015

Nickel ions selectively inhibit lipopolysaccharide-induced interleukin-6 production by decreasing its mRNA stability.

PLoS One 2015 5;10(3):e0119428. Epub 2015 Mar 5.

Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan.

Nickel (Ni) ions easily elute from many alloys and elicit inflammation and allergies. Previous studies have shown that infections due to the implantation of medical devices cause inflammation and enhance the elution of Ni ions (Ni²⁺). However, cross-talk between infection- and Ni²⁺-induced signaling pathways has not yet been elucidated in detail. In the present study, we investigated the effects of Ni2+ on the lipopolysaccharide (LPS)-induced production of cytokines in a LPS-induced air pouch-type inflammation model in BALB/c mice and the murine macrophage cell line RAW264. We demonstrated that Ni²⁺ inhibited the LPS-induced production of interleukin (IL)-6, but not that of tumor necrosis factor (TNF)-α both in vivo and in vitro. This inhibitory effect was also observed with cobalt ion (Co²⁺), but not with chloride ion (Cl⁻), zinc ion (Zn²⁺), or palladium ion (Pd²⁺), and was highly selective to the production of IL-6. Ni²⁺ did not inhibit the activation of ERK1/2, p38 MAPK, or JNK. Although Ni²⁺ decreased IL-6 mRNA levels, it failed to inhibit the LPS-induced activation of the IL-6 promoter. An experiment using actinomycin D, a transcription inhibitor, revealed that Ni²⁺ decreased the stability of IL-6 mRNA. Moreover, Ni²⁺ inhibited the LPS-induced expression of Arid5a, but not regnase-1. These results demonstrated that Ni²⁺ may have selectively inhibited the LPS-induced production of IL-6 by decreasing the Arid5a-dependent stabilization of IL-6 mRNA.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0119428PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351189PMC
January 2016
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