The inhibitory role of intracellular free zinc in the regulation of <i>Arg-1</i> expression in interleukin-4-induced activation of M2 microglia
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- Takaaki Aratake
- Department of Pharmacology, Kochi Medical School, Kochi University , Kohasu, Okoh-cho, Nankoku 783-8505, . Fax: +81-88-880-2328; Tel: +81-88-880-2327
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- Youichirou Higashi
- Department of Pharmacology, Kochi Medical School, Kochi University , Kohasu, Okoh-cho, Nankoku 783-8505, . Fax: +81-88-880-2328; Tel: +81-88-880-2327
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- Yusuke Ueba
- Department of Neurosurgery, Kochi Medical School, Kochi University , Kohasu, Okoh-cho, Nankoku 783-8505,
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- Tomoya Hamada
- Department of Pharmacology, Kochi Medical School, Kochi University , Kohasu, Okoh-cho, Nankoku 783-8505, . Fax: +81-88-880-2328; Tel: +81-88-880-2327
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- Takahiro Shimizu
- Department of Pharmacology, Kochi Medical School, Kochi University , Kohasu, Okoh-cho, Nankoku 783-8505, . Fax: +81-88-880-2328; Tel: +81-88-880-2327
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- Shogo Shimizu
- Department of Pharmacology, Kochi Medical School, Kochi University , Kohasu, Okoh-cho, Nankoku 783-8505, . Fax: +81-88-880-2328; Tel: +81-88-880-2327
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- Toshio Yawata
- Department of Neurosurgery, Kochi Medical School, Kochi University , Kohasu, Okoh-cho, Nankoku 783-8505,
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- Tetsuya Ueba
- Department of Neurosurgery, Kochi Medical School, Kochi University , Kohasu, Okoh-cho, Nankoku 783-8505,
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- Motoaki Saito
- Department of Pharmacology, Kochi Medical School, Kochi University , Kohasu, Okoh-cho, Nankoku 783-8505, . Fax: +81-88-880-2328; Tel: +81-88-880-2327
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説明
<jats:title>Abstract</jats:title> <jats:p>Microglia, the resident immune cells of the central nervous system, can display a pro-inflammatory M1 phenotype or an anti-inflammatory M2 phenotype. Arginase (Arg)-1 expressed in interleukin-4 (IL-4)-induced M2 microglia reduces nitric oxide (NO) production by competing with inducible NO synthase for l-arginine, which contributes to the attenuation of brain inflammation. Although previous studies have indicated that brain zinc promotes M1 activation, the effect of zinc on M2 microglial activation remains to be determined. In the present study, murine primary microglia treated with 10 ng mL−1 IL-4 exhibited increased Arg-1 mRNA expression and levels of intracellular free zinc. Chelation of this increased intracellular free zinc by the cell permeable zinc chelator N,N,N′,N′-tetrakis-(2-pyridylmethyl)ethylenediamine (TPEN) aggravated the IL-4-induced mRNA expression and enzymatic activity of Arg-1. However, the cell impermeable zinc chelator CaEDTA had no effect on Arg-1 expression or cytosolic levels of free zinc in IL-4-induced M2-polarized microglia. Furthermore, treatment with IL-4 resulted in upregulation of phagocytic activity in microglia, while administration of TPEN abolished IL-4-induced phagocytic activity. Moreover, this effect was reversed vial-arginine supplementation. These findings suggest that IL-4 induces an increase in intracellular free zinc in microglia, which may act as a negative regulator of IL-4-induced Arg-1 expression, and that such negative regulation is essential for microglial phagocytic activity.</jats:p>
収録刊行物
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- Metallomics
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Metallomics 10 (10), 1501-1509, 2018-09-03
Oxford University Press (OUP)
