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Relevance of the mevalonate biosynthetic pathway in the regulation of bone marrow mesenchymal stromal cell-mediated effects on T-cell proliferation and B-cell survival.
MedLine Citation:
PMID:  20884711     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Bone marrow mesenchymal stromal cells can suppress T-lymphocyte proliferation but promote survival of normal and malignant B cells, thus representing a possible target for new therapeutic schemes. Here we defined the effects of cholesterol synthesis inhibitors on the interaction between these mesenchymal stromal cells and T or B lymphocytes.
DESIGN AND METHODS: We exposed mesenchymal stromal cells to inhibitors, such as fluvastatin, of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase, responsible for the synthesis of mevalonate, the precursor of cholesterol. Also, these cells were treated with manumycin A, a farnesyl transferase inhibitor which blocks the mevalonate-dependent isoprenylation of small guanosin triphosphate binding proteins. First, mesenchymal stromal cell morphology, cytoskeleton assembly, cell cycle, survival and cytokine production were evaluated. Then, these cells were co-cultured with either T or B lymphocytes and we analyzed: 1) the inhibition of T-cell proliferation to mitogenic stimuli; 2) B-cell survival.
RESULTS: Fluvastatin altered the assembly of actin microfilaments, inactivated RhoA guanosin triphosphate binding protein, inhibited the S-phase of the cell cycle, induced apoptosis in a small fraction of cells but preserved cytokine production. Preincubation of mesenchymal stromal cells with fluvastatin, or manumycin A, down-regulated the expression of adhesion molecules, reduced cell-to-cell interactions and prevented the inhibition exerted by these stromal cells on CD3/T-cell receptor-induced lymphocyte proliferation. Mevalonic acid could revert morphological, phenotypic and functional effects of fluvastatin. Finally, fluvastatin significantly reduced the mesenchymal stromal cells-mediated rescue of B cells in the presence of dexamethasone, although it did not function in the absence of corticosteroids.
CONCLUSIONS: Fluvastatin-mediated effects on bone marrow mesenchymal stromal cells were conceivably due to the inhibition of isoprenylation of small guanosin triphosphate binding proteins, occurring for the lack of mevalonate. Altogether these findings suggest that drugs acting on the mevalonate biosynthetic pathway can regulate mesenchymal stromal cell-induced T-cell suppression and B-lymphocyte survival.
Authors:
Alessandra Musso; Maria Raffaella Zocchi; Alessandro Poggi
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-09-30
Journal Detail:
Title:  Haematologica     Volume:  96     ISSN:  1592-8721     ISO Abbreviation:  Haematologica     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2011-01-03     Completed Date:  2011-05-26     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  0417435     Medline TA:  Haematologica     Country:  Italy    
Other Details:
Languages:  eng     Pagination:  16-23     Citation Subset:  IM    
Affiliation:
Molecular Oncology and Angiogenesis, Department of Translational Oncology, National Institute for Cancer Research Genoa, Genoa, Italy. alessandro.poggi@istge.it
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MeSH Terms
Descriptor/Qualifier:
Actins / metabolism
Acyl Coenzyme A / antagonists & inhibitors
Apoptosis / drug effects
B-Lymphocytes / drug effects,  metabolism*
Blotting, Western
Bone Marrow Cells / drug effects,  metabolism*
Cell Communication / drug effects
Cell Cycle / drug effects
Cell Proliferation / drug effects
Cells, Cultured
Coculture Techniques
Fatty Acids, Monounsaturated / pharmacology
Flow Cytometry
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
Indoles / pharmacology
Lymphocyte Activation / drug effects
Mesenchymal Stromal Cells / drug effects,  metabolism*
Mevalonic Acid / metabolism*
Protein Prenylation
Stromal Cells / drug effects,  metabolism*
T-Lymphocytes / drug effects,  metabolism*
rhoA GTP-Binding Protein
Chemical
Reg. No./Substance:
0/Actins; 0/Acyl Coenzyme A; 0/Fatty Acids, Monounsaturated; 0/Hydroxymethylglutaryl-CoA Reductase Inhibitors; 0/Indoles; 150-97-0/Mevalonic Acid; 1553-55-5/3-hydroxy-3-methylglutaryl-coenzyme A; 4L066368AS/fluvastatin; EC 3.6.5.2/rhoA GTP-Binding Protein
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