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J. Microbiol. Biotechnol. 2007; 17(2): 348-358

Published online February 28, 2007

Copyright © The Korean Society for Microbiology and Biotechnology.

Functions of Metallothionein Generating Interleukin-10-Producing Regulatory CD4+ T Cells Potentiate Suppression of Collagen-Induced Arthritis

Huh, Sungjin , Kyuheon Lee 1, Hye-Sun Yun 1, Doo-Jin Paik 1, Jung Mogg Kim 2 and Jeehee Youn 3*

Department of Anatomy and Cell Biology,, 1Department of Biomedical Sciences and Institute of Biomedical Sciences, and, 2Department of Microbiology, College of Medicine, Hanyang University, Seoul, Korea, 3Department of Anatomy and Cell Biology Department of Biomedical Sciences and Institute of Biomedical Sciences

Abstract

Metallothionein, a cysteine-rich stress response protein that is naturally induced by a variety of immunologic stressors, has been shown to suppress autoimmune disorders through mechanisms not yet fully defined. In the present study, we examined the underlying mechanisms by which metallothionein might mediate such regulation of autoimmunity. $Na\ddot{i}ve\;CD4^+$ T cells from metallothionein-deficient mice differentiated to produce significantly less IL-10, $TGF-{\gamma}$, and repressor of GATA, but more $IFN-{\gamma}$ and T-bet, when compared with those from wild-type mice. The levels of IL-4 and GATA-3 production were not different between the two groups of mice. Conversely, treatment with exogenous metallothionein during the priming phase drove $na\ddot{i}ve$ wild-type $CD4^+\;T$ cells to differentiate into cells producing more IL-10 and $TGF-{\beta}$, but less $IFN-{\gamma}$ than untreated cells. Metallothionein-primed cells were hyporesponsive to restimulation, and suppressive to T cell proliferation in an IL-10-dependent manner. Lymphocytes from metallothionein-deficient mice displayed significantly elevated levels of AP-1 and JNK activities in response to stimulation compared with those from wild-type controls. Importantly, transgenic mice overexpressing metallothionein exhibited significantly reduced susceptibility to collagen-induced arthritis and enhanced IL-10 level in the serum, relative to their nontransgenic littermates. Taken together, these data suggest that metallothionein is able to promote the generation of IL-10-and $TGF-{\beta}$-producing type 1 regulatory T-like cells by downregulating JNK-dependent AP-1 activity. Thus, metallothionein may play an important role in the regulation of Th1-dependent autoimmune arthritis, and may represent both a potential target for therapeutic manipulation and a critical element in the diagnostic assessment of disease potential.

Keywords: Metallothionein, interleukin-10, regulatory T cell, arthiritis autoimmunity