Zinc-binding metallothioneins are key modulators of IL-4 production by basophils

Tsukasa Ugajin; Keigo Nishida; Satoru Yamasaki; Junko Suzuki; Masaharu Mita; Masato Kubo; Hiroo Yokozeki; Toshio Hirano

doi:10.1016/j.molimm.2015.03.002

Zinc-binding metallothioneins are key modulators of IL-4 production by basophils

Mol Immunol. 2015 Aug;66(2):180-8. doi: 10.1016/j.molimm.2015.03.002. Epub 2015 Mar 22.

Authors

Tsukasa Ugajin¹, Keigo Nishida², Satoru Yamasaki³, Junko Suzuki⁴, Masaharu Mita⁵, Masato Kubo⁶, Hiroo Yokozeki⁷, Toshio Hirano⁸

Affiliations

¹ Department of Dermatology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan; Laboratory for Homeostatic Network, RIKEN Research Center for Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
² Laboratory for Homeostatic Network, RIKEN Research Center for Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan; Laboratory of Immune Regulation, Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, 3500-3 Minamitamagaki-cho, Suzuka, Mie 513-8670, Japan. Electronic address: [email protected].
³ Laboratory for Homeostatic Network, RIKEN Research Center for Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
⁴ Center for Environmental Risk Research, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506, Japan.
⁵ Laboratory Animal Research Center, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
⁶ Division of Molecular Pathology, Research Institute for Biomedical Science, Tokyo University of Science, 2669 Yamazaki, Noda, Chiba 278-0022, Japan; Laboratory for Cytokine Regulation, RIKEN Research Center for Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
⁷ Department of Dermatology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
⁸ Osaka University, 1-1 Yamada-oka, Suita, Osaka 565-0871, Japan. Electronic address: [email protected].

PMID: 25801306
DOI: 10.1016/j.molimm.2015.03.002

Abstract

Zinc (Zn) is an essential nutrient, and Zn deficiency causes immunodeficiency and skin disorders. Basophils express FcɛRI on their surface and release multiple mediators after receptor cross-linking, including large amounts of IL-4. However, the mechanisms involved in the FcɛRI-mediated regulation of basophil IL-4 production are currently unclear. Here, we show that the Zn-binding metallothionein (MT) proteins are essential for the FcɛRI-induced basophil production of IL-4. Basophils from MT-I/II(-/-) mice produced significantly less FcɛRI-induced IL-4 than did wild-type basophils. The MTs were involved in maintaining intracellular Zn levels, thereby regulated the calcineurin activity and nuclear factor of activated T-cell (NFAT)-mediated IL-4 production. These results suggest that the MT-dependent control of Zn homeostasis is a novel mechanism for regulating basophil IL-4 production.

Keywords: Basophil; IL-4 signal transduction; Metallothionein; Zinc.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Basophils / cytology
Basophils / immunology*
Basophils / metabolism
Calcineurin / genetics
Calcineurin / immunology
Calcineurin / metabolism
Gene Expression Regulation
Homeostasis / immunology
Interleukin-4 / genetics
Interleukin-4 / immunology*
Interleukin-4 / metabolism
Metallothionein / deficiency
Metallothionein / genetics
Metallothionein / immunology*
Mice
Mice, Inbred C57BL
Mice, Knockout
NFATC Transcription Factors / genetics
NFATC Transcription Factors / immunology
NFATC Transcription Factors / metabolism
Primary Cell Culture
Protein Binding
Receptors, IgE / genetics
Receptors, IgE / immunology*
Receptors, IgE / metabolism
Signal Transduction
Zinc / immunology*
Zinc / metabolism

Substances

Mt2 protein, mouse
NFATC Transcription Factors
Receptors, IgE
metallothionein-1, mouse
Interleukin-4
Metallothionein
Calcineurin
Zinc