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KMID : 0545120070170020348
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Journal of Microbiology and Biotechnology
2007 Volume.17 No. 2 p.348 ~ p.358
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Functions of Metallothionein Generating Interleukin-10-Producing Regulatory CD4+ T Cells Potentiate Suppression of Collagen-Induced Arthritis
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Huh Sung-Jin
Lee Kyu-Heon
Yun Hye-Sun
Paik Doo-Jin
Kim Jung-Mogg
Youn Jee-Hee
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Abstract
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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. Naive CD4+ T cells from metallothionein-deficient mice differentiated to produce significantly less IL-10, TGF-γ, and repressor of GATA, but more IFN-γ 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 naive wild-type CD4+ T cells to differentiate into cells producing more IL-10 and TGF-β, but less IFN-γ 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 collageninduced 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-β-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.
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KEYWORD
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Metallothionein, interleukin-10, regulatory T cells, arthritis, autoimmunity
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