Protection against a lethal dose of endotoxin by an inhibitor of tumour necrosis factor processing.
Tumour necrosis factor (tumour necrosis factor-alpha/cachectin) plays a critical role in certain physiological defensive responses but causes severe damage to the host organism when produced in excess. There are two forms of tumour necrosis factor, a type II membrane protein of relative molecular mass 26,000 (26K) and a soluble, 17K form generated from the cell-bound protein by proteolytic cleavage. The two forms of tumour necrosis factor and lymphotoxin-alpha (tumour necrosis factor-beta/lymphotoxin), a related protein, have similar but apparently not identical biological activities. A therapeutic agent which inhibited the release of tumour necrosis factor, but did not reduce the cell-associated activity or the level of lymphotoxin-alpha, might preserve the benefits of these cytokines while preventing tumour necrosis factor-induced damage. Here we describe a potent inhibitor of tumour necrosis factor processing and report that it protects mice from a lethal dose of endotoxin.
Immunex Research and Development Corporation, Seattle, Washington 98101.
K M
KM
Mohler
P R
PR
Sleath
J N
JN
Fitzner
D P
DP
Cerretti
M
M
Alderson
S S
SS
Kerwar
D S
DS
Torrance
C
C
Otten-Evans
T
T
Greenstreet
K
K
Weerawarna
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008233:Lymphotoxin-alpha / Q000378:metabolism; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity
D006877:Hydroxamic Acids; D008233:Lymphotoxin-alpha; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D008666:Metalloendopeptidases