Cytokine-mediated modulation of MMPs and TIMPs in multipotential neural precursor cells.
Recent studies have implicated the inflammatory process during experimental allergic encephalomyelitis (EAE) in triggering migration and differentiation of transplanted neural precursors cells (NPCs) into the inflamed white matter. The pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma are key factors in the pathogenesis of brain inflammation in EAE and were shown to enhance NPCs migration in vitro. As cell migration is dependent on extracellular matrix remodeling, involving proteolytic enzyme members of the matrix metalloproteinase (MMPs) family, we characterized the profile of expression of MMPs and their endogenous inhibitors (TIMPs) in rat NPCs, and evaluated the effects of TNF-alpha, IFN-gamma and IFN-beta, a clinically proven modulator of brain inflammation, on the expression of these molecules. Newborn rat striatal NPCs were expanded in spheres as nestin+, PSA-NCAM+ and NG2(-) cells, which can differentiate into astrocytes, oligodendrocytes and neurons. NPCs' gelatinase activities of MMP-2 and MMP-9, as determined by zymography, were increased by TNF-alpha, and to a lesser extent by IFN-gamma. Semi-quantitative RT-PCR indicated that TNF-alpha also upregulated MMP-9 mRNA levels. IFN-beta suppressed the TNF-alpha-induced levels of secreted MMP-9 and MMP-2, while enhancing the expression of TIMP-1 and TIMP-2 mRNA. These results suggest that MMPs activity is induced in NPCs by pro-inflammatory cytokines to mobilize them for promoting reparative processes. IFN-beta, on the other hand, appears to have an anti-proteolytic influence that may attenuate such NPC-mediated repair processes.
Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. tamir@hadassah.org.il
Tamir
T
Ben-Hur
Yaara
Y
Ben-Yosef
Rachel
R
Mizrachi-Kol
Ofra
O
Ben-Menachem
Ariel
A
Miller
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000502:physiology*; D015536:Down-Regulation / Q000276:immunology; D004790:Enzyme Induction / Q000276:immunology; D018093:Gelatinases / Q000096:biosynthesis / Q000378:metabolism; D016899:Interferon-beta / Q000502:physiology; D007371:Interferon-gamma / Q000502:physiology; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011917:Rats, Inbred Lew; D013234:Stem Cells / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D019714:Tissue Inhibitor of Metalloproteinases / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology
D016207:Cytokines; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta; D007371:Interferon-gamma; D018093:Gelatinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9