Essential role for ERK mitogen-activated protein kinase in matrix metalloproteinase-9 regulation in rat cortical astrocytes

Matrix metalloproteinases (MMPs) contribute to the pathophysiology of brain injury and inflammation but little is known about their regulatory signaling pathways in brain cells. Here we examine the role of mitogen-activated protein (MAP) kinase pathways in MMP-9 regulation in cortical rat astrocytes. The protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) induced MMP-9 but not MMP-2 secretion as measured by gelatin zymography. Northern blot and RT-PCR analysis showed that MMP-9 responses occurred at the mRNA level. Although PMA increased phosphorylation in all three major MAP kinase pathways (ERK, p38 MAP kinase, and JNK), only inhibition of the ERK pathway by the MEK/ERK inhibitor U0126 (0.1-10 microM) significantly reduced MMP-9 upregulation, even when treatment was delayed for 4 h after PMA exposure. Inhibitors of p38 MAP kinase (SB203580) and JNK (SP600125) had no effect. This PKC pathway was compared to a cytokine response by exposing astrocytes to TNFalpha, which also activated MAP kinase and induced MMP-9 upregulation. But in this case, all three MAP kinase inhibitors (U0126, SB203580, and SP600125) reduced TNFalpha-induced MMP-9 upregulation. Taken together, these results suggest that the ERK MAP kinase is essential for MMP-9 upregulation via PKC and cytokine pathways in astrocytes.