title: Production of matrix metalloproteinase-9 in early stage B-CLL: suppression by interferons.
abstract: Besides vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), matrix metalloproteinases (MMPs) play critical roles in angiogenesis, tumor invasion and metastasis. Increased angiogenesis is observed in chronic B lymphocytic leukemia (B-CLL) and published data reported VEGF and bFGF production in this disease. The purpose of this study was to investigate MMP expression in early stage B-CLL. Elevated MMP-9 concentrations were detected by ELISA in the sera of B-CLL patients (median level 250 ng/ml) compared with healthy donors (67 ng/ml) (P < 0.0001), and immunostaining with antibodies against MMP-9 and B cell antigens (CD19, CD23) substantiated the presence of MMP-9 in tumoral B lymphocytes. By using RT-PCR, ELISA and zymography experiments, we confirmed that B-CLL cells expressed and released the pro-form of MMP-9 with Mr 92 kDa (158-1300 pg/ml/10(6) cells/48 h), p-aminophenylmercuric acetate generating a 82 kDa active form. In contrast, the production of MMP-9 by normal counterpart B cells was significantly low (28-169 pg/ml/10(6)cells/48 h). Moreover, B-CLL culture supernatants contained bFGF (median levels 17 pg/ml/10(6) cells/48 h), VEGF (1.4 pg/ml/10(6) cells/48 h) and TNF-alpha (0.2 pg/ml/10(6) cells/48 h). TNF-alpha and VEGF antibodies blocked MMP-9 at the mRNA and protein levels. Interferons (IFNs) type I or type II repressed MMP-9 gelatinolytic activity in a dose and time dependency, and this was reflected by a parallel inhibition of MMP-9 mRNA and protein. IFNs however did not affect the production of bFGF, VEGF and TNF-alpha. Together, our data show that B-CLL lymphocytes synthesize MMP-9 and emphasize the specific inhibitory actions of IFNs on its expression.
authors: Unité 365 INSERM, Section de Recherche, Institut Curie, Pavillon Pasteur, 26 rue d'Ulm, 75248 Paris cedex 05, France.
authors: B
authors: B
authors: Bauvois
authors: J
authors: J
authors: Dumont
authors: C
authors: C
authors: Mathiot
authors: J-P
authors: JP
authors: Kolb
mesh_terms: D016022:Case-Control Studies; D018929:Cell Culture Techniques; D003470:Culture Media / Q000737:chemistry / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000378:metabolism / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology; D016898:Interferon-alpha / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology* / Q000473:pathology; D008222:Lymphokines / Q000187:drug effects / Q000378:metabolism / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000097:blood; D061965:Matrix Metalloproteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D003470:Culture Media; D016228:Endothelial Growth Factors; D007370:Interferon Type I; D016898:Interferon-alpha; D008222:Lymphokines; D061965:Matrix Metalloproteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D007371:Interferon-gamma; D020780:Matrix Metalloproteinase 9