Pharmacologic modulation in vitro of human histamine-induced suppressor cell activity

Abstract

Various metabolic inhibitors and agents which increase intracellular cyclic nucleotide levels were investigated for their effects on the generation of suppressor cells in a co-culture system. Human blood mononuclear cells (MNC) were stimulated with histamine (10 −3 – 10 −5M) for 24 h in the absence or presence of other agents, washed, co-cultured with lectin-stimulated autologous MNC and suppression of 3H-thymidine uptake was measured. The generation of histamine-induced suppressor cells was shown to require active cellular metabolism since inhibitors of transcription (1 μg ml −1 actinomycin D), translation (5 μg ml −1 puromycin and 1 μg ml −1 cycloheximide), oxidative phosphorylation (10 −2 sodium azide) and glycolysis (10 −2M 2-deoxyglucose) significantly reduced their activity. Inhibitors of cytoskeletal function such as cytochalasin B (5 μg ml −1) and colchicine (3 × 10 −5M) also markedly reduced suppressor activity. There was no apparent requirement for DNA synthesis in the generation of suppressor cells since treatment of MNC with mitomycin C (50 μg ml −1) had no effect on suppression. Incubation of MNC with cAMP-elevating agents (10 −3M dibuteryl cAMP and 3 × 10 −5M papaverine) for 2 h resulted in augmented suppressor activity while longer incubations (24 h) resulted in reduced function. Incubation (2 – 24 h) of MNC with cGMP-elevating agents (10 −3M dibuteryl cGMP and 10 −5M imidazole) had no effect on suppressor cell activity. These agents may interfere with critical lymphocyte - macrophage interactions (lymphokine/monokine synthesis and/or secretion) that are required for intact suppressor responses.