Ornithine decarboxylase interferes with macrophage-like differentiation and matrix metalloproteinase-9 expression by tumor necrosis factor alpha via NF-kappaB.
Ornithine decarboxylase (ODC), a tumor promoter, provokes cell proliferation, and inhibits cell death; but the mechanism involved in cell differentiation remains unknown. Herein, we examine whether it functions during macrophage-like differentiation. Previous studies reveal that ODC, a rate-limiting enzyme of polyamine biosynthesis, and polyamines are involved in restraining immune response in activated macrophage. By using 12-O-tetradecanoylphorbol-13-acetate (TPA)-differentiated human promyelocytic HL-60 and promonocytic U-937 cells, we discover that polyamines block the expression, secretion and activation of MMP-9. Meanwhile conventional expression of ODC represses tumor necrosis factor-alpha (TNF-alpha) expression and nuclear factor-kappaB (NF-kappaB) activation as well as MMP-9 enzyme activity. Following stimulation by TNF-alpha, the secretion of MMP-9 is restored in ODC-overexpressed cells. In addition, the NF-kappaB inhibitors (pyrrolidinedithiocarbamate, BAY-11-7082 and lactacystin) suppress the TPA-induced MMP-9 enzyme activity. Concurrently, both the irreversible inhibitor of ODC, alpha-difluoromethylornithine, and TNF-alpha could not recover MMP-9 activation following NF-kappaB inhibitor treatment in parental cells. Furthermore, ODC could directly inhibit and attenuate NF-kappaB DNA binding and transcriptional activation. Therefore, we suggest that ODC inhibits the TNF-alpha-elevated MMP-9 activation via NF-kappaB as TPA-induced macrophage-like differentiation and this interrupting mechanism may provide a new conceivable resolution why leukemia is poorly differentiated besides atypical growth.
Liao
Ya-Fan
YF
Department of Life Sciences, National Chung-Hsing University, Taichung, Taiwan, ROC.
Hung
Hui-Chih
HC
Hsu
Pei-Chen
PC
Kao
Ming-Ching
MC
Hour
Tzyh-Chyuan
TC
Tsay
Gregory J
GJ
Liu
Guang-Yaw
GY
D001483:Base Sequence; D002454:Cell Differentiation / Q000502:physiology*; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D018922:HL-60 Cells; D006801:Humans; D008264:Macrophages / Q000166:cytology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D016328:NF-kappa B / Q000502:physiology*; D009955:Ornithine Decarboxylase / Q000378:metabolism* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D017931:DNA Primers; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D020780:Matrix Metalloproteinase 9; D009955:Ornithine Decarboxylase