p38 MAP kinase regulates rapid matrix metalloproteinase-9 release from eosinophils.
Eosinophils constitutively produce and store matrix metalloproteinase-9 (MMP-9), a protease implicated in tissue remodeling observed in asthma. In this study, we examined the rapid release of stored MMP-9 from eosinophils following stimulation with either tumor necrosis factor-alpha (TNF-alpha or the bacterial product fMLP. TNF-alpha induced rapid and robust pro-MMP-9 release from eosinophils. MMP-9 could be detected in the cell-free supernatant as early as 15min after stimulation. Rapid MMP-9 release was similarly induced by fMLP. TNF-alpha stimulation activated the mitogen-activated protein (MAP) kinases p38 MAP kinase and extracellular signal-regulated kinase-2 (Erk-2) at times and concentrations similar to that observed for MMP-9 release. Using pharmacological inhibitors, we found that TNF-alpha-stimulated MMP-9 release was mediated by p38 MAP kinase, but not Erk-1/2. Signaling through p38 MAP kinase may represent a universal mechanism for MMP-9 release from eosinophils, as fMLP-induced MMP-9 release was also regulated by p38 MAP kinase.
Wiehler
Shahina
S
Departments of Physiology and Biophysics, University of Calgary, Calgary, Alta., Canada T2N 4N1.
Cuvelier
Susan L
SL
Chakrabarti
Subhadeep
S
Patel
Kamala D
KD
D015703:Antigens, CD / Q000378:metabolism; D015153:Blotting, Western; D002474:Cell-Free System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004804:Eosinophils / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D007962:Leukocytes / Q000378:metabolism; D020935:MAP Kinase Signaling System; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000737:chemistry / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D015398:Signal Transduction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D015703:Antigens, CD; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D009240:N-Formylmethionine Leucyl-Phenylalanine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9