Functions of metallothionein generating interleukin-10-producing regulatory CD4+ T cells potentiate suppression of collagen-induced arthritis.
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. Naïve 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 naïve 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.
Huh
Sungjin
S
Department of Anatomy and Cell Biology, College of Medicine, Hanyang University, Seoul, Korea.
Lee
Kyuheon
K
Yun
Hye-Sun
HS
Paik
Doo-Jin
DJ
Kim
Jung Mogg
JM
Youn
Jeehee
J
D000818:Animals; D001169:Arthritis, Experimental / Q000517:prevention & control*; D016753:Interleukin-10 / Q000096:biosynthesis*; D008668:Metallothionein / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D016328:NF-kappa B / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics; D020825:T-Box Domain Proteins / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D000098815:T-bet Transcription Factor
D016328:NF-kappa B; D012097:Repressor Proteins; C406863:Rog protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D008668:Metallothionein