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 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.
Marikovsky
Moshe
M
Department of Animal Sciences, Faculty of Agricultural, Food, and Environmental Quality Sciences, Hebrew University of Jerusalem, Rehovot, Israel. marikovs@agri.huji.ac.il
Ziv
Vered
V
Nevo
Nava
N
Harris-Cerruti
Catherine
C
Mahler
Ori
O
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000517:prevention & control; D002478:Cells, Cultured; D017364:Collagenases / Q000378:metabolism; D003300:Copper / Q000494:pharmacology; D004221:Disulfiram / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D004789:Enzyme Activation / Q000276:immunology; D005260:Female; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000201:enzymology / Q000276:immunology; D007249:Inflammation / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology; D051381:Rats; D011917:Rats, Inbred Lew; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D015854:Up-Regulation / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D008222:Lymphokines; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D003300:Copper; D013482:Superoxide Dismutase; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D017364:Collagenases; D004221:Disulfiram