Exogenous nitric oxide inhibits shedding of ADAM17 substrates.
Both ADAM17, the secretase responsible for the shedding of ectodomains of numerous membrane proteins including TNF and its receptors, as well as nitric oxide synthesized by inducible nitric oxide synthase play regulatory roles in inflammation and tumor progression. We analyzed the effect of endogenous and exogenous nitric oxide on the expression and activity of ADAM17 in murine endothelial cells and a monocyte/macrophage cell line. We found that endogenous nitric oxide influenced neither ADAM17 mRNA level nor the shedding of two ADAM17 substrates, TNF and TNFR1. Exogenous NO significantly diminished the release of TNF and TNFR1 without affecting the ADAM17 transcript level. Our data seem contrary to a previous report that showed the activation of ADAM17 by nitric oxide (Zhang et al., 2000, J Biol Chem 275: 15839-15844). We discuss potential mechanisms of NO-mediated inhibition of ectodomain shedding and possible reasons of discrepancy between our results and the previous report.
Bzowska
Monika
M
Department of Cell Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland.
Stalińska
Krystyna
K
Mezyk-Kopeć
Renata
R
Wawro
Karolina
K
Duda
Katarzyna
K
Das
Sudipta
S
Bereta
Joanna
J
D051722:ADAM Proteins / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D000954:Antigens, Surface; D002460:Cell Line; D002461:Cell Line, Transformed; D042783:Endothelial Cells / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D004792:Enzyme Precursors; D005434:Flow Cytometry; D007700:Kinetics; D008264:Macrophages / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D045726:Metalloproteases / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000378:metabolism / Q000494:pharmacology*; D014176:Protein Biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000737:chemistry / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism
D000954:Antigens, Surface; D004792:Enzyme Precursors; D020030:Nitric Oxide Donors; D012333:RNA, Messenger; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D045726:Metalloproteases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse