SOLUBLE TNF BINDING-PROTEINS MODULATE THE NEGATIVE INOTROPIC PROPERTIES OF TNF-ALPHA IN-VITRO

Soluble tumor necrosis factor (TNF) binding proteins (TNF-BPs) were ch aracterized with respect to their capacity to modulate the negative in otropic properties of TNF-alpha in isolated contracting cardiac myocyt es. Three TNF-BPs were evaluated: two natural monomeric human TNF mono meric binding proteins, TNF-BP1 and TNF-BP2, and sTNFR:Fc, a dimer of two molecules of human TNF-BP2 linked by the Fc portion of the human i mmunoglobulin G1 molecule. When TNF-alpha (25 pM) was allowed to form TNF-BP-TNF-alpha complexes, the negative inotropic effects of TNF-alph a were completely prevented by ''neutralizing concentrations'' of TNF- BPs, whereas lesser concentrations of TNF-BPs only partially attenuate d the negative inotropic effects of TNF-alpha. The dimeric binding pro tein sTNFR:Fc was more effective on a molar basis than either of the m onomeric binding proteins (TNF-BP1 or TNF-BP2) with respect to blockin g the negative inotropic effects of TNF-alpha. When cardiac myocytes t hat had been treated with TNF-alpha (25 pM) were exposed to neutralizi ng concentrations of TNF-BP1, TNF-BP2, and sTNFR:Fc, the negative inot ropic effects were completely reversed within 30 min. Thus these studi es show for the first time that TNF-BPs are sufficient to prevent, as well as reverse, the negative inotropic properties of TNF-alpha in vit ro.