Targeting the T-cell membrane type-1 matrix metalloproteinase-CD44 axis in a transferred type 1 diabetes model in NOD mice

Sanford Research, University of South Dakota, Sioux Falls, SD 57105
Experimental and therapeutic medicine (Impact Factor: 1.27). 02/2013; 5(2):438-442. DOI: 10.3892/etm.2012.821
Source: PubMed


This study tested the hypothesis that membrane-tethered type-1 matrix metalloproteinase (MT1-MMP)-induced proteolysis of T cell CD44 is important for defining the migration and function of autoreactive T cells, including diabetogenic, insulin-specific and K(d)-restricted IS-CD8(+) cells. To confirm the importance of MT1-MMP proteolysis of CD44 in type 1 diabetes (T1D), the anti-diabetic effects of three MMP inhibitors (3(S)-2,2-dimethyl-4[4-pyridin-4-yloxy-benzenesulfonyl]-thiomorpholine-3-carboxylic acid hydroxamate [AG3340], 2-(4-phenoxyphenylsulfonylmethyl) thiirane [SB-3CT] and epigallocatechin-3-gallate [EGCG]) were compared using an adoptive diabetes transfer model in non-obese diabetic (NOD) mice. Only AG3340 was capable of inhibiting both the activity of MT1-MMP and the shedding of CD44 in T cells; and the transendothelial migration and homing of IS-CD8(+) T cells into the pancreatic islets. SB-3CT and EGCG were incapable of inhibiting T cell MT1-MMP efficiently. As a result, AG3340 alone, but not SB-3CT or EGCG, delayed the onset of transferred diabetes in NOD mice. In summary, the results of the present study emphasize that the MT1-MMP-CD44 axis has a unique involvement in T1D development. Accordingly, we suggest that a potent small-molecule MT1-MMP antagonist is required for the design of novel therapies for T1D.

Download full-text


Available from: Alex Y Strongin, Feb 12, 2014
  • Source
    • "To this end, a cluster of differentiation (CD)133(+) cell population isolated from U87 glioblastoma cells was recently shown to be highly responsive to S1P signaling and to require the cooperation of membrane-associated, type-I (MT1)-MMP,34 a cell surface MMP shown to be efficiently targeted by EGCG.35,36 Whether such cooperative MT1-MMP to S1P signaling is physiologically relevant was further explored in alternate circulating cell models, such as T cells37 and bone marrow-derived mesenchymal stromal cells,38 where MT1-MMP functions were targeted by EGCG. Evidence possibly supporting such a cooperative MT1-MMP to S1P signaling axis was recently based on the fact that S1P induced the association of MT1-MMP with p130Cas in endothelial cells39 and that this interaction represents a novel mechanism in the macrophage cell fusion machinery.40 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Macrophage chemotaxis followed by blood–brain barrier transendothelial migration is believed to be associated with inflammation in the central nervous system. Antineuroinflammatory strategies have identified the dietary-derived epigallocatechin-3-gallate (EGCG) as an efficient agent to prevent neuroinflammation-associated neurodegenerative diseases by targeting proinflammatory mediator signaling. Methods Given that high levels of sphingosine kinase and its product, sphingosine-1-phosphate (S1P), are present in brain tumors, we used quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and immunoblotting to test whether EGCG may impact on S1P receptor gene expression and prevent S1P response in undifferentiated and in terminally differentiated macrophages. Results Promyelomonocytic human leukemia (HL)-60 cells were differentiated into macrophages, and S1P triggered phosphorylation in extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and P38 mitogen-activated protein kinase (MAPK) intracellular signaling, as shown by Western blot analysis. Pretreatment of cells with EGCG prior to differentiation inhibited the response to S1P in all three pathways, while EGCG abrogated P38 MAPK phosphorylation when present only during differentiation. Terminally-differentiated macrophages were, however, insensitive to EGCG treatment. Using qRT-PCR, gene expression of the S1P receptors S1P1, S1P2, and S1P5 was predominantly induced in terminally-differentiated macrophages, while the S1P2 was decreased by EGCG treatment. Conclusion Our data suggest that diet-derived EGCG achieves efficient effects as a preventive agent, targeting signaling pathways prior to cell terminal differentiation. Such properties could impact on cell chemotaxis through the blood–brain barrier and prevent cancer-related neuroinflammation.
    Full-text · Article · May 2014 · OncoTargets and Therapy
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: CSF-2 and CSF-3 confer proangiogenic and immunomodulatory properties to mesenchymal stromal cells (MSCs). Results: Transcriptional regulation of CSF-2 and CSF-3 in concanavalin A-activated MSCs requires MT1-MMP signaling and is inhibited by EGCG. Conclusion: The chemopreventive properties of diet-derived EGCG alter MT1-MMP-mediated intracellular signaling. Significance: Pharmacological targeting of MSCs proangiogenic functions may prevent their contribution to tumor development. Epigallocatechin gallate (EGCG), a major form of tea catechins, possesses immunomodulatory and antiangiogenic effects, both of which contribute to its chemopreventive properties. In this study, we evaluated the impact of EGCG treatment on the expression of colony-stimulating factors (CSF) secreted from human bone marrow-derived mesenchymal stromal cells (MSCs), all of which also contribute to the immunomodulatory and angiogenic properties of these cells. MSCs were activated with concanavalin A (ConA), a Toll-like receptor (TLR)-2 and TLR-6 agonist as well as a membrane type 1 matrix metalloproteinase (MT1-MMP) inducer, which increased granulocyte macrophage-CSF (GM-CSF, CSF-2), granulocyte CSF (G-CSF, CSF-3), and MT1-MMP gene expression. EGCG antagonized the ConA-induced CSF-2 and CSF-3 gene expression, and this process required an MT1-MMP-mediated sequential activation of the Src and JAK/STAT pathways. Gene silencing of MT1-MMP expression further demonstrated its requirement in the phosphorylation of Src and STAT3, whereas overexpression of a nonphosphorylatable MT1-MMP mutant (Y573F) abrogated CSF-2 and CSF-3 transcriptional increases. Given that MSCs are recruited within vascularizing tumors and are believed to contribute to tumor angiogenesis, possibly through secretion of CSF-2 and CSF-3, our study suggests that diet-derived polyphenols such as EGCG may exert chemopreventive action through pharmacological targeting of the MT1-MMP intracellular signaling.
    Full-text · Article · Apr 2013 · Journal of Biological Chemistry
  • Source

    Full-text · Article · Mar 2014
Show more