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      Metallothionein as an Anti-Inflammatory Mediator

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          Abstract

          The integration of knowledge concerning the regulation of MT, a highly conserved, low molecular weight, cystein-rich metalloprotein, on its proposed functions is necessary to clarify how MT affects cellular processes. MT expression is induced/enhanced in various tissues by a number of physiological mediators. The cellular accumulation of MT depends on the availability of cellular zinc derived from the diet. MT modulates the binding and exchange/transport of heavy metals such as zinc, cadmium, or copper under physiological conditions and cytoprotection from their toxicities, and the release of gaseous mediators such as hydroxyl radicals or nitric oxide. In addition, MT reportedly affects a number of cellular processes, such as gene expression, apoptosis, proliferation, and differentiation. Given the genetic approach, the apparently healthy status of MT-deficient mice argues against an essential biological role for MT; however, this molecule may be critical in cells/tissues/organs in times of stress, since MT expression is also evoked/enhanced by various stresses. In particular, because metallothionein (MT) is induced by inflammatory stress, its roles in inflammation are implied. Also, MT expression in various organs/tissues can be enhanced by inflammatory stimuli, implicating in inflammatory diseases. In this paper, we review the role of MT of various inflammatory conditions.

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            Metallothionein: an intracellular protein to protect against cadmium toxicity.

            Metallothioneins (MT) are low-molecular-weight, cysteine-rich, metal-binding proteins. MT genes are readily induced by various physiologic and toxicologic stimuli. Because the cysteines in MT are absolutely conserved across species, it was suspected that the cysteines are necessary for function and MT is essential for life. In attempts to determine the function(s) of MT, studies have been performed using four different experimental paradigms: (a) animals injected with chemicals known to induce MT; (b) cells adapted to survive and grow in high concentrations of MT-inducing toxicants; (c) cells transfected with the MT gene; and (d) MT-transgenic and MT-null mice. Most often, results from studies using the first three approaches have indicated multiple functions of MT in cell biology: MT (a) is a "storehouse" for zinc, (b) is a free-radical scavenger, and (c) protects against cadmium (Cd) toxicity. However, studies using MT-transgenic and null mice have not strongly supported the first two proposed functions but strongly support its function in protecting against Cd toxicity. Repeated administration of Cd to MT-null mice results in nephrotoxicity at one tenth the dose that produces nephrotoxicity in control mice. Human studies indicate that 7% of the general population have renal dysfunction from Cd exposure. Therefore, if humans did not have MT, "normal" Cd exposure would be nephrotoxic to humans. Thus, it appears that during evolution, the ability of MT to protect against Cd toxicity might have taken a more pivotal role in the maintenance of life processes, as compared with its other proposed functions (i.e. storehouse for zinc and free radical scavenger).
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              The elusive function of metallothioneins.

              Biochemistry and genetics are both required to elucidate the function of macromolecules. There is no question that metallothioneins (MTs) have unique biochemical properties, but genetic experiments have not substantiated the importance of MTs under physiological conditions. Even after thousands of studies describing the structure, biochemical characteristics, tissue distribution, induction, and consequences of genetic disruption and deliberate overexpression, the evolutionary forces that led to the initial appearance, gene duplications, and nearly ubiquitous expression of MTs remain enigmatic.
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                Author and article information

                Journal
                Mediators Inflamm
                MI
                Mediators of Inflammation
                Hindawi Publishing Corporation
                0962-9351
                1466-1861
                2009
                11 May 2009
                : 2009
                : 101659
                Affiliations
                1Environmental Health Sciences Division, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba 305-8506, Japan
                2Department of Veterinary Pathology, Faculty of Agriculture, Tottori University, 101 Kozan-cho, Tottori 680-8553, Japan
                3Department of Hygienics, Aichi Pharmaceutical University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya 464-0037, Japan
                Author notes

                Recommended by Fulvio D'Acquisto

                Article
                10.1155/2009/101659
                2679981
                19436762
                154d98d8-af38-464f-bd47-9e636865cec0
                Copyright © 2009 Ken-ichiro Inoue et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 10 October 2008
                : 26 February 2009
                Categories
                Review Article

                Immunology
                Immunology

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