Cellular signalling and free-radical modulating activities of of the novelpeptidomimetic L-glutamyl-histamine

A. novel histamine-containing peptidomimetic, L-glutamyl-histamine (L-Glu-H ist), has been synthesized and characterized as a possible cytokine mimic w hich might lead to cellular responses of improved specificity. The energy-m inimized 3-D conformations of L-Glu-Hist derived:from its chemical structur e stabilize Fe2+-chelating complexes. L-Glu-Hist concentration-dependently accelerates a decrease in ferrous iron in ferrous sulfate solution and show s ferroxidase-like activity at;concentrations less than 3 mM in the phenant hroline assay, whereas in, the concentration range 3-20 mM it restricts, th e availability of Fe2+ to phenanthroline by chelation of iron ions. At-low concentrations (less than or about 1 mM), L-Glu-Hist stimulates peroxidatio n of phosphatidylcholine in liposomes catalyzed by a superoxide anion radic al (O-2(radical anion))-generating system (Fe2+ + ascorbate) and, at,high c oncentrations:.(similar to 10 mM), it suppresses lipid peroxidation (LPO) i n liposomes. O-2(radical anion) stimulation,of LPO by L-Glu-Hist is related to its ability at low concentrations (similar to 0.05 mM) to release O-2(r adical anion) free radicals as determined, by the superoxide dismutase-inhi bitable reductive of cytochrome c. The release of O-2(radical anion) by L-G lu-Hist might result from its: ferroxidase-like activity, while its inhibit ion of LPO is due to chelation of Fe2+,prevention of the formation of free radicals,and degradation of lipid hydroperoxides at,5-20 mM L-Glu-Hist conc entrations. L-Glu-Hist releases O-2(radical anion) at concentrations which stimulate [H-3]thymidine incorporation into DNA and proliferation of mouse spleen lymphocytes and also of mononuclear cells from human blood. The indu ction of lymphocyte proliferation by L-Glu-Hist is dose-dependent in the 0. 01-0.05 mM concentration-range, although,the maximal stimulation:of LPO,in the O-2(radical anion)-dependent system is observed at higher L-Glu-Hist co ncentrations (similar to 1 mM). Thus, ow concentrations of oxygen free radi cals released by L-Glu-Hist may provide a, very fast,, specific, and sensit ive trigger for lymphocyte proliferation and immunoregulation.