Cathepsin-G and leukocyte elastase inactivate human tumor necrosis factor and lymphotoxin.
The addition of either cathepsin-G or leukocyte elastase to endotoxin-stimulated human peripheral blood monocytes decreased the immunoreactive tumor necrosis factor (TNF) detected in culture supernatants in a concentration-dependent manner. Both enzymes also induced a loss of supernatant cytolytic activity as determined on the WEHI-164 target cell line. Incubation of recombinant human TNF and lymphotoxin (LT) with either cathepsin-G or leukocyte elastase resulted in a loss of cytokine bioactivity. Examination of enzyme-treated recombinant cytokines by gel electrophoresis revealed that cathepsin-G cleaved LT into a 12.6-kDa fragment and leukocyte elastase fragmented LT into a 14.1-kDa product. On Western blots cathepsin-G and leukocyte elastase degraded TNF into 11- and 7.6-kDa fragments, respectively. Incubating leukocyte elastase with plasma elastase inhibitor alpha-1-antitrypsin prevented the loss of recombinant TNF bioactivity and blocked the degradation of this cytokine. This study suggests that two of the most abundant neutrophil proteases, cathepsin-G and leukocyte elastase, may be important regulators of TNF and LT bioactivity.
Scuderi
P
P
Arizona Cancer Center, Tucson.
Nez
P A
PA
Duerr
M L
ML
Wong
B J
BJ
Valdez
C M
CM
D000328:Adult; D015153:Blotting, Western; D056649:Cathepsin G; D002403:Cathepsins / Q000494:pharmacology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D019272:Leukocyte Elastase; D008233:Lymphotoxin-alpha / Q000378:metabolism*; D009504:Neutrophils / Q000502:physiology; D010196:Pancreatic Elastase / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D012697:Serine Endopeptidases; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D000515:alpha 1-Antitrypsin / Q000494:pharmacology
D007375:Interleukin-1; D008233:Lymphotoxin-alpha; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D000515:alpha 1-Antitrypsin; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase