TNF and the Molecular Pathogenesis of Shock 
been released. These studies might lead to better 
therapies for shock and other disorders. Gluco- 
corticoid hormones (e.g., prednisone, dexameth- 
asone, and Cortisol) have long been used as anti- 
inflammatory drugs. One of their principal 
effects appears to be a blockade of TNF biosynthe- 
sis.,, which depends upon inhibition of both TNF 
gene transcription and mRNA translation. Other 
drugs of a class known as phosphodiesterase in- 
hibitors (e.g., theophylline, caffeine, and pen- 
toxifylline) also block TNF biosynthesis, achiev- 
ing their effect by preventing TNF mRNA 
accumulation. They appear to function at a dif- 
ferent locus than do glucocorticoids. We have 
shown that the two classes of drugs when com- 
bined exert a synergistic effect. 
Recently the cell-surface receptor for TNF was 
cloned in a number of laboratories. We have engi- 
neered a recombinant molecule in which the TNF 
receptor is attached to a portion of a normal anti- 
body, yielding a new protein molecule in which 
two TNF-binding sites are expressed. This biva- 
lent TNF-binding protein strongly inhibits the bi- 
ological effects of TNF, is highly stable in vivo, 
and may be produced in large quantities by re- 
combinant techniques. We anticipate that this 
type of molecule will allow a thorough investiga- 
tion of the many effects of TNF in health and dis- 
ease and may also be useful as a therapeutic tool. 
Of particular interest will be its use in studies of 
TNF production and action in the thymus and in 
the placenta. 
36 
