AUTOCRINE REGULATION OF MATRIX METALLOPROTEINASE-9 GENE-EXPRESSION AND SECRETION BY TUMOR-NECROSIS-FACTOR-ALPHA (TNF-ALPHA) IN NB4 LEUKEMIC-CELLS - SPECIFIC INVOLVEMENT OF TNF RECEPTOR-TYPE-1
Mg. Ismair et al., AUTOCRINE REGULATION OF MATRIX METALLOPROTEINASE-9 GENE-EXPRESSION AND SECRETION BY TUMOR-NECROSIS-FACTOR-ALPHA (TNF-ALPHA) IN NB4 LEUKEMIC-CELLS - SPECIFIC INVOLVEMENT OF TNF RECEPTOR-TYPE-1, Leukemia, 12(7), 1998, pp. 1136-1143
Matrix metalloproteinases have been reported to be involved in tumor c
ell invasion and metastasis. Dissemination of malignant cells in acute
myeloid leukemia (AML) may be mediated by similar mechanisms. Here, w
e report, that the t(15/17)(+) acute promyelocytic leukemia (APL) cell
line NB4 constitutively expresses and releases the proenzyme form of
matrix metalloproteinase-9 (MMP-9, 92 kDa type IV collagenase/gelatina
se, gelatinase B), as well as tissue inhibitor of metalloproteinases-1
(TIMP-1). Both proteins were identified by N-terminal amino acid sequ
ence analysis after purification using gelatin Sepharose affinity chro
matography. Whereas 12-O-tetradecanoylphorbol-13 acetate (TPA) increas
ed both MMP-9 and TIMP-1 mRNA levels, tumor necrosis factor-alpha (TNF
-alpha) stimulated only MMP-9 gene expression in a dose- and time-depe
ndent manner. Neutralizing monoclonal antibodies (MoABs) to TNF-alpha
(anti-TNF-alpha) decreased the constitutive and TPA-dependent expressi
on of MMP-9 but did not influence TIMP-1 expression, either in unstimu
lated or in TPA-treated NB4 cells. FACS analyses showed that NB4 cells
express both TNF receptor 1 (TNF-R1) and TNF-R2 to a similar extent.
Blocking MoABs against TNF-R 1 (anti-TNF-R1) decreased the constitutiv
e expression of MMP-9, whereas anti-TNF-R2 had almost no effect. Our r
esults show, that in NB4 cells the expression of MMP-9 but not of TIMP
-1 is maintained by autocrine stimulation with TNF-alpha. Thus, leukem
ic cells may be enabled to leave the bone marrow and infiltrate periph
eral tissues by a dysfunction in the regulation of the MMP-9:TIMP-1 eq
uilibrium, possibly triggered through autostimulation by TNF-alpha.