MAP Kinase Activation is Required for the MMP-9 Induction by TNF-Stimulation

MMP-9 is a metalloproteinase capable of basement membrane degradation in vivo. Expression of MMP-9 can be found in normal conditions such as trophoblasts, osteoclasts, and leukocytes and their precursors. They also occur as well as in pathological conditions, such as the invasive growth of primary tumors, metastasis, angiogenesis, rheumatoid arthritis, and periodontal diseases. MMP-9 upregulation can be highly induced by a wide range of agents. These agents include growth factors, cytokines, cell-cell, and cell-ECM adhesion molecules, and agents altering cell shape. Here, we observed that TNF-$\alpha$ stimulated human monocytic cell line, HL-60 produced MMP-9 in a dose and time dependent manner. Real time PCR results indicated transcriptional upregulation of MMP-9 as early as 3 h post TNF-$\alpha$ stimulation. To investigate the signaling pathway underlined in TNF-$\alpha$ induced MMP-9 expression, three MAP kinase inhibitors were added to cells 1 h prior to TNF-$\alpha$ treatment. The ERK inhibitor completely abolished MMP-9 expression by TNF-$\alpha$. But neither p38 MAP kinase nor JNK inhibitor had an effect on TNF-$\alpha$ induced MMP-9 expression, suggesting that ERK activation is required for the MMP-9 induction by TNF-$\alpha$. Taken together, we found that TNF-$\alpha$ stimulation facilitates ERK activation, which results in the transcriptional upregulation of MMP-9 gene and subsequent MMP-9 production and secretion.