Peptidoglycan of Staphylococcus aureus induces enhanced levels of matrix metalloproteinase-9 in human blood originating from neutrophils.
Enhanced plasma levels of matrix metalloproteinase 9 (MMP-9) detected in patients with severe sepsis are thought to contribute to the development of organ dysfunction in endotoxemia. We have recently reported that peptidoglycan, the major wall component of gram-positive bacteria, increases MMP-9 levels in lung and liver and organ injury in the rat. Thus far, it is unclear whether MMP-9 is part of the septic response to peptidoglycan in human blood. The aim of the present study was to examine the regulation of MMP-9 by peptidoglycan in human leukocytes. The addition of peptidoglycan to whole human blood caused enhanced levels of MMP-9 after 1 h of incubation (306 vs. 75 ng/mL, P < or = 0.05) and onward, as measured by enzyme-linked immunoabsorbant assay. In neutrophil cultures, MMP-9 values increased significantly after 30 min of incubation with peptidoglycan (242 vs. 121 ng/mL, P < or = 0.05), whereas muramyl dipeptide had no effect. In contrast, adherent monocytes released insignificant amounts of MMP-9. To examine whether the released MMP-9 resulted from de novo synthesis, intracellular and secreted MMP-9 was measured during stimulation of neutrophils. The total MMP-9 values (the sum of intracellular and secreted MMP-9) before and after stimulation were mainly unaltered. The enhanced MMP-9 levels induced by peptidoglycan was attenuated by inhibitors of p38 mitogen-activated protein kinases (MAPK), (SB202190, 25 microM) and ERK1/2 (PD98059, 25 microM) and inhibitors of Src Tyrosine kinase (PP2, 5 microM) and PI3-K (LY294002, 25 microM).
Wang
Yun Yong
YY
University of Oslo, Family Division Rikshospitalet, Institute for Surgical Research, Oslo, 0027, Norway.
Myhre
Anders E
AE
Pettersen
Solveig J
SJ
Dahle
Maria K
MK
Foster
Simon J
SJ
Thiemermann
Christoph
C
Bjørnland
Kristin
K
Aasen
Ansgar O
AO
Wang
Jacob E
JE
D002867:Chromones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019446:Endotoxemia; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005419:Flavonoids / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007249:Inflammation; D007700:Kinetics; D007962:Leukocytes / Q000201:enzymology; D008070:Lipopolysaccharides / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000097:blood*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009504:Neutrophils / Q000201:enzymology* / Q000378:metabolism; D010457:Peptidoglycan / Q000737:chemistry / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000378:metabolism*; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
C412373:AG 1879; D002867:Chromones; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D008070:Lipopolysaccharides; D009025:Morpholines; D010457:Peptidoglycan; D011725:Pyridines; D011743:Pyrimidines; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019061:src-Family Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one