Cu/Zn Superoxide Dismutase Plays Important Role in Immune Response

Activation of macrophages leads to the secretion of cytokines and enzymes that shape the inflammatory response and increase metabolic processes. This, in turn, results in increased production of reactive oxygen species. The role of Cu/Zn superoxide dismutase (SOD-1), an important enzyme in cellular...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2003-03, Vol.170 (6), p.2993-3001
Main Authors: Marikovsky, Moshe, Ziv, Vered, Nevo, Nava, Harris-Cerruti, Catherine, Mahler, Ori
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Anti-Inflammatory Agents, Non-Steroidal - administration & dosage
Anti-Inflammatory Agents, Non-Steroidal - antagonists & inhibitors
Anti-Inflammatory Agents, Non-Steroidal - pharmacology
Antioxidants - pharmacology
Arthritis, Experimental - prevention & control
Cells, Cultured
Collagenases - metabolism
Copper - pharmacology
Disulfiram - administration & dosage
Disulfiram - antagonists & inhibitors
Disulfiram - pharmacology
Endothelial Growth Factors - antagonists & inhibitors
Endothelial Growth Factors - metabolism
Enzyme Activation - immunology
Female
Humans
Hypersensitivity, Delayed - enzymology
Hypersensitivity, Delayed - immunology
Inflammation - enzymology
Inflammation - immunology
Inflammation - metabolism
Inflammation - prevention & control
Intercellular Signaling Peptides and Proteins - metabolism
Lipopolysaccharides - pharmacology
Lymphokines - antagonists & inhibitors
Lymphokines - metabolism
Macrophage Activation - drug effects
Macrophage Activation - immunology
Macrophages, Peritoneal - drug effects
Macrophages, Peritoneal - enzymology
Macrophages, Peritoneal - immunology
Macrophages, Peritoneal - metabolism
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Transgenic
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinases - metabolism
Mitogen-Activated Protein Kinases - physiology
Rats
Rats, Inbred Lew
Superoxide Dismutase - biosynthesis
Superoxide Dismutase - physiology
Tumor Necrosis Factor-alpha - antagonists & inhibitors
Tumor Necrosis Factor-alpha - metabolism
Tumor Necrosis Factor-alpha - physiology
Up-Regulation - immunology
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors
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Summary:Activation of macrophages leads to the secretion of cytokines and enzymes that shape the inflammatory response and increase metabolic processes. This, in turn, results in increased production of reactive oxygen species. The role of Cu/Zn superoxide dismutase (SOD-1), an important enzyme in cellular oxygen metabolism, was examined in activated peritoneal elicited macrophages (PEM) and in several inflammatory processes in vivo. LPS and TNF-alpha induced SOD-1 in PEM. SOD-1 induction by LPS was mainly via extracellular signal-regulated kinase-1 activation. Transgenic mice overexpressing SOD-1 demonstrated a significant increase in the release of TNF-alpha and of the metalloproteinases MMP-2 and MMP-9 from PEM. Disulfiram (DSF), an inhibitor of SOD-1, strongly inhibited the release of TNF-alpha, vascular endothelial growth factor, and MMP-2 and MMP-9 from cultured activated PEM. These effects were prevented by addition of antioxidants, further indicating involvement of reactive oxygen species. In vivo, transgenic mice overexpressing SOD-1 demonstrated a 4-fold increase in serum TNF-alpha levels and 2-fold stronger delayed-type hypersensitivity reaction as compared with control nontransgenic mice. Conversely, oral administration of DSF lowered TNF-alpha serum level by 4-fold, lowered the delayed-type hypersensitivity response in a dose-dependent manner, and significantly inhibited adjuvant arthritis in Lewis rats. The data suggest an important role for SOD-1 in inflammation, establish DSF as a potential inhibitor of inflammation, and raise the possibility that regulation of SOD-1 activity may be important in the treatment of immune-dependent pathologies.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.170.6.2993