Metallothionein suppresses collagen-induced arthritis via induction of TGF-beta and down-regulation of proinflammatory mediators.
Metallothionein is a low molecular weight, cysteine-rich, stress response protein that can act as an antioxidant and as an immunosuppressive agent in instances of antigen-dependent adaptive immunity. In this context, we assessed the therapeutic potential and mechanisms of action of metallothionein in a collagen-induced arthritis model. Repeated administration of metallothionein-I + II during the course of disease dramatically reduced the incidence and severity of the disease. Joint tissues isolated from boostered paws of metallothionein-I + II-treated mice expressed significantly reduced levels of proinflammatory mediators, such as tumour necrosis factor (TNF)-alpha and cyclooxygenase-2, when compared with those of control-treated mice. Lymph node cells obtained from metallothionein-I + II -injected mice exhibited a significant decrease in the proliferative response and a remarkable increase in tumour growth factor (TGF)-beta production in response to type II collagen. Taken together, these results suggest that metallothionein-I + II promote the development of type II collagen-specific, TGF-beta-producing cells to antagonize the expansion of arthritogenic cells. This could lead to local suppression of inflammatory responses by inhibiting the expression of proinflammatory molecules. Thus, this study demonstrates the suppressive effects of metallothionein on collagen-induced arthritis, and indicates that there may be a potential therapeutic application for manipulation of metallothionein during the treatment of autoimmune disorders.
Youn
J
J
Institute of Biomedical Science and Department of Anatomy and Cell Biology, College of Medicine, Hanyang University, Seoul, Korea.
Hwang
S-H
SH
Ryoo
Z-Y
ZY
Lynes
M A
MA
Paik
D-J
DJ
Chung
H-S
HS
Kim
H-Y
HY
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D024043:Collagen Type II / Q000276:immunology; D015536:Down-Regulation / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D018836:Inflammation Mediators / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008668:Metallothionein / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008811:Mice, Inbred DBA; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*
D024043:Collagen Type II; D016166:Free Radical Scavengers; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D016212:Transforming Growth Factor beta; D008668:Metallothionein