Modulation of autocrine TNF-alpha-stimulated matrix metalloproteinase 9 (MMP-9) expression by mitogen-activated protein kinases in THP-1 monocytic cells.
Matrix metalloproteinase 9 (MMP-9) is implicated in various physiological processes by its ability to degrade the extracellular matrix (ECM) and process multiple regulatory proteins. Normally, MMP-9 expression is tightly controlled in cells. Sustained or enhanced MMP-9 secretion, however, has been demonstrated to contribute to the pathophysiology of numerous diseases, including arthritis and tumor progression, rendering this enzyme a major target for clinical interventions. Here we show that constitutive MMP-9 secretion was abrogated in THP-1 monocytic leukemia cells by addition of neutralizing antibodies against tumor necrosis factor alpha (TNF-alpha) or TNF receptor type 1 (TNF-R1), as well as by inhibition of TNF-alpha converting enzyme (TACE). This indicates that MMP-9 production in these cells is maintained by autocrine stimulation, with TNF-alpha acting via TNF-R1. To investigate the intracellular signaling routes involved in MMP-9 gene transcription, cells were treated with different inhibitors of major mitogen-activated protein kinase (MAPK) pathways. Interruption of the extracellular signal-regulated kinase pathway 1/2 (ERK1/2) using PD98059 significantly downregulated constitutive MMP-9 release. In contrast, blockage of p38 kinase activity by addition of SB203580 or SB202190, as well as inhibition of c-Jun N-terminal kinase (JNK) using L-JNK-I1, clearly augmented MMP-9 expression and secretion by an upregulation of ERK1/2 phosphorylation. Moreover, exogenously added TNF-alpha augmented MMP-9 synthesis and secretion in THP-1 cells via enhancement of ERK1/2 activity. Taken together, our results indicate that ERK1/2 activity plays a pivotal role in TNF-alpha-induced MMP-9 production and demonstrate its negative modulation by p38 and JNK activity. These findings suggest ERK1/2 rather than p38 and JNK as a reasonable target to specifically block MMP-9 expression using MAPK inhibitors in therapeutic applications.
Heidinger
Michael
M
Division of Clinical Chemistry and Clinical Biochemistry, Surgical Department of the Ludwig-Maximilians-University, D-80336 Munich, Germany.
Kolb
Helmut
H
Krell
Hans-Willi
HW
Jochum
Marianne
M
Ries
Christian
C
D019898:Autocrine Communication / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D015536:Down-Regulation; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D009000:Monocytes / Q000378:metabolism*; D010766:Phosphorylation; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020780:Matrix Metalloproteinase 9