Metallothionein suppresses collagen-induced arthritis via induction of TGF-<b>β</b>and down-regulation of proinflammatory mediators

Youn, Jeehee; Hwang, Sun‐Hee; Ryoo, Zae-Young; Lynes, Michael A.; Paik, Doo Jin; Chung, Hyunji; Kim, H.-Y.

doi:10.1046/j.1365-2249.2002.01922.x

Cited by 63 publications

(53 citation statements)

References 51 publications

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“…MTs possibly function at the later stage of Tr1 cell development by their temporal expression profile in Tr1 cells. It has been described that MT proteins play significant roles during different inflammatory conditions, such as collageninduced arthritis (CIA) (26) or EAE (27), but the function of MTs within different cell compartments varies. During CNS inflammation, it has been reported that MTs play an important role for EAE recovery, because MT proteins were found to be elevated within the CNS, specifically in astrocytes and activated macrophages (27).…”

Section: Discussionmentioning

confidence: 99%

Metallothioneins negatively regulate IL-27–induced type 1 regulatory T-cell differentiation

Pot

Apétoh

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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IL-27–induced type 1 regulatory T (Tr1) cells suppress autoimmunity by producing IL-10. Signal transducer and activator of transcription (STAT) 1 and STAT3 have been described as key transcription factors that promote IL-10 secretion from Tr1 cells induced by IL-27. However, the molecular pathways for negatively regulating Tr1 cell differentiation remain elusive. Here, we show that IL-27 induces metallothioneins (MTs) that in turn prevent Tr1 cell development. MT expression leads to the reduction of STAT1 and STAT3 phosphorylation under Tr1 differentiation condition, resulting in impaired IL-10 production. Accordingly, Tr1 cells derived from MT-deficient mice showed an increased ability to produce IL-10 and potently suppress experimental autoimmune encephalomyelitis upon adoptive transfer. Moreover, activation of STAT1 and/or STAT3 can overcome the suppression of IL-10 by MTs, indicating a dynamic balance between STATs and MTs in regulating IL-10 during Tr1 cell differentiation.

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Section: Discussionmentioning

confidence: 99%

Metallothioneins negatively regulate IL-27–induced type 1 regulatory T-cell differentiation

Pot

Apétoh

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Joint sections (5 m) were stained with H&E and examined for the histological changes of inflammation, pannus formation, cartilage, and bone damage. Arthritic changes in the ankle were scored as previously described: 0, normal; 1, weak leukocyte infiltration but no erosion; 2, modest infiltration and weak erosion; 3, severe infiltration and invasion of bones; and 4, loss of bone integrity (30).…”

Section: Clinical and Histological Assessment Of Arthritismentioning

confidence: 99%

Targeted Disruption of Leukotriene B4 Receptors BLT1 and BLT2: A Critical Role for BLT1 in Collagen-Induced Arthritis in Mice

Shao

Prete

Bock

et al. 2006

The Journal of Immunology

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Leukotriene B4 mediates diverse inflammatory diseases through the G protein-coupled receptors BLT1 and BLT2. In this study, we developed mice deficient in BLT1 and BLT2 by simultaneous targeted disruption of these genes. The BLT1/BLT2 double-deficient mice developed normally and peritoneal exudate cells showed no detectable responses to leukotriene B4 confirming the deletion of the BLT1/BLT2 locus. In a model of collagen-induced arthritis on the C57BL/6 background, the BLT1/BLT2−/− as well as the previously described BLT1−/− animals showed complete protection from disease development. The disease severity correlated well with histopathology, including loss of joint architecture, inflammatory cell infiltration, fibrosis, pannus formation, and bone erosion in joints of BLT1/BLT2+/+ animals and a total absence of disease pathology in leukotriene receptor-deficient mice. Despite these differences, all immunized BLT1−/− and BLT1/BLT2−/− animals had similar serum levels of anti-collagen Abs relative to BLT1/BLT2+/+ animals. Thus, BLT1 may be a useful target for therapies directed at treating inflammation associated with arthritis.

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“…Other reports demonstrate that systemic administration of TGF-␤ profoundly antagonizes the development of polyarthritis in susceptible rats by reducing inflammatory cell infiltration and joint erosion (7). Moreover, metallothionein suppresses collageninduced arthritis via induction of TGF-␤ and down-regulation of proinflammatory mediators (8). Although these observations provide insight into the systemic, multidimensional immunoregulatory effects of TGF-␤, little is known about the mechanisms by which an individual TGF-␤-suppressed leukocyte fails to initiate or continue its assigned immune function.…”

mentioning

confidence: 99%

TGF-β Inhibits IL-2 Production and Promotes Cell Cycle Arrest in TCR-Activated Effector/Memory T Cells in the Presence of Sustained TCR Signal Transduction

Das¹,

Levine

2008

The Journal of Immunology

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TGF-β signaling is critical for controlling naive T cell homeostasis and differentiation; however, the biological and biochemical changes induced by TGF-β in effector/memory T cells are poorly defined. We show that although TGF-β inhibits effector/memory peripheral blood T lymphoblast proliferation and IL-2 production, the intensity and kinetics for TCR-induced global tyrosine phosphorylation are markedly increased compared with that in untreated cells or naive T cells. After TCR ligation, tyrosine phosphorylation of proximal tyrosine kinases and docking proteins like linker for activation of T cells is maintained for >30 min in TGF-β-primed cells compared with untreated cells where phosphorylation of these targets returned to basal levels by 10 min. Extended phosphorylation of linker for activation of T cells in treated peripheral blood T selectively prolongs ERK 1/2 signaling and phospholipase C-γ1 activation leading to increased Ca2+ flux. A kinase/phosphatase imbalance could not account for extended phosphorylation as CD45R, SHP-1, and SHP-2 expression remains unaltered. The contradiction between prolonged signal transduction and inhibition of proliferation is partially explained by the observation that TGF-β priming results in ERK 1/2-independent p21 induction and decreased cyclin D1 expression leading to accumulation of T cells in G0/G1 phases of the cell cycle and cell cycle arrest. Despite inhibition of T cell function by TGF-β priming, TCR and cytokine signaling pathways are intact and selectively extended, suggesting that suppression in the effector/memory T cell is mediated by reprogramming signal transduction, rather than its inhibition as in the naive T cell.

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Metallothionein suppresses collagen-induced arthritis via induction of TGF-βand down-regulation of proinflammatory mediators

Cited by 63 publications

References 51 publications

Metallothioneins negatively regulate IL-27–induced type 1 regulatory T-cell differentiation

Metallothioneins negatively regulate IL-27–induced type 1 regulatory T-cell differentiation

Targeted Disruption of Leukotriene B4 Receptors BLT1 and BLT2: A Critical Role for BLT1 in Collagen-Induced Arthritis in Mice

TGF-β Inhibits IL-2 Production and Promotes Cell Cycle Arrest in TCR-Activated Effector/Memory T Cells in the Presence of Sustained TCR Signal Transduction

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