Phosphatidic acid as a regulator of matrix metalloproteinase-9 expression via the TNF-α signaling pathway

• Published in: FEBS letters 2007-02, Vol.581 (4), p.787-793
• Main Authors: Lee, Jin-Gu, Lee, Sun-Hye, Park, Dae-Weon, Bae, Yoe-Sik, Yun, Sung-Su, Kim, Jae-Ryong, Baek, Suk-Hwan
• Format: Article
• Language: English
• Subjects: 1,2-dioctanoyl-glycero-3-phosphate; Animals; c-jun amino-terminal kinase; C8-PA; DAG; diacylglycerol; ECM; Enzyme Activation - drug effects; ERK; extracellular matrix; extracellular signal-regulated kinase; Gene Expression Regulation, Enzymologic - drug effects; interleukin; JNK; lipopolysaccharide; LPS; lysoPA; lysophosphatidic acid; Macrophages - drug effects; Macrophages - enzymology; Macrophages - secretion; mammalian target of rapamycin; MAPK; matrix metalloproteinase; Matrix Metalloproteinase 9 - metabolism; Matrix metalloproteinase-9; Mice; mitogen activated protein kinase; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; MMP; mTOR; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphatidic acid; Phosphatidic Acids - pharmacology; phospholipase D; Phosphorylation - drug effects; PLD; Receptors, Tumor Necrosis Factor, Type I - metabolism; Receptors, Tumor Necrosis Factor, Type II - metabolism; Signal Transduction - drug effects; TNF; TNF receptor; TNFR; tumor necrosis factor; Tumor necrosis factor- α; Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - secretion
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2007.01.048

Phosphatidic acid (PA) is implicated in pathophysiological processes associated with cellular signaling events and inflammation, which include the expressional regulation of numerous genes. Here, we show that PA stimulation increases matrix metalloproteinase-9 (MMP-9) expression in macrophages through tumor necrosis factor (TNF)-α signaling. We performed antibody array analysis on proteins from macrophages stimulated with PA. PA was found to induce the production of TNF-α, but not of TNF receptor (TNFR)1 and TNFR2 in a time-dependent manner and stimulated significant, though delayed, MMP-9 expression. PA induced the phosphorylations of both ERK1/2 and p38, but not of c-jun amino-terminal kinase. Moreover, only ERK1/2 inhibition by U0126 suppressed PA-induced TNF-α production and MMP-9 expression. Neutralizing TNF-α, TNFR1 or TNFR2 antibodies significantly suppressed PA-induced MMP-9 expression, suggesting that the production of TNF-α in response to PA preceded the expression of MMP-9. Moreover, lipopolysaccharide-induced PA also led to TNF-α release and resulted in MMP-9 expression. Taken together, these observations suggest that PA may play a role in MMP-9 regulation through ERKs/TNF-α/TNFRs-dependent signaling pathway.