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Essential role for ERK mitogen‐activated protein kinase in matrix metalloproteinase‐9 regulation in rat cortical astrocytes
Author(s) -
Arai Ken,
Lee SunRyung,
Lo Eng H.
Publication year - 2003
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.10255
Subject(s) - mapk/erk pathway , mitogen activated protein kinase kinase , mitogen activated protein kinase , protein kinase c , biology , map kinase kinase kinase , p38 mitogen activated protein kinases , downregulation and upregulation , kinase , microbiology and biotechnology , protein kinase a , map2k7 , ask1 , mapk14 , signal transduction , mitogen activated protein kinase 3 , c raf , cyclin dependent kinase 9 , cyclin dependent kinase 2 , biochemistry , gene
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 μM) 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 TNFα, which also activated MAP kinase and induced MMP‐9 upregulation. But in this case, all three MAP kinase inhibitors (U0126, SB203580, and SP600125) reduced TNFα‐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. © 2003 Wiley‐Liss, Inc.