STUDIES OF THE SYNTHESIS, IMMUNOLOGY, AND CYTOTOXICITY OF A CYCLIC OCTAPEPTIDE CORRESPONDING TO TNF-ALPHA-(59-66)

In an attempt to investigate possible binding domains of the tumor nec rosis factors (TNF), we have previously synthesized a cyclic hexapepti de corresponding to murine TNF-(127-132) (cTNF-1).(3) In this report, we describe the synthesis and biological activity of another cyclic oc tapeptide corresponding to human TNF-alpha-(59-66) (cTNF-2). The desig n of these cyclic peptides is based on their high sequence homology wi th corresponding fragments of human TNF-alpha or TNF-beta. Similar to cTNF-1,(3) the cyclic octapeptide cTNF-2 displayed low in vitro cytoto xicity against human HeLa and HEP-2 cell lines. The cyclic peptides cT NF-2 and cTNF-1 were then tested for the induction of interleukin-l (I L-1) production from human peripheral blood mononuclear cells and mono cytes in vitro. At low concentrations, the IL-1 levels induced by thes e cyclic peptides were similar to that of recombinant TNF-alpha. Howev er, the IL-1 production by cTNF-2 stimulation was dose-dependently inc reased and reached that of a lipopolysaccharide (LPS; 0.1 mu g/mL) lev el. These findings suggest that the fragments corresponding to human T NF-alpha-(59-66) and murine TNF-(127-132) may represent certain bindin g domains of the tumor necrosis factors that elicit IL-1 production.