Pharmacologic modulation in vitro of human histamine-induced suppressor cell activity.
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(-5)M) for 24 h in the absence or presence of other agents, washed, co-cultured with lectin-stimulated autologous MNC and 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 microgram ml-1 actinomycin D), translation (5 micrograms ml-1 puromycin and 1 microgram ml-1 cycloheximide), oxidative phosphorylation (10(-2)M sodium azide) and glycolysis (10(-2)M 2-deoxyglucose) significantly reduced their activity. Inhibitors of cytoskeletal function such as cytochalasin B (5 micrograms ml-1) and colchicine (3 X 10(-5)M) 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 micrograms ml-1) had no effect on suppression. Incubation of MNC with cAMP-elevating agents (10(-3)M dibuteryl cAMP and 3 X 10(-5)M 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(-3)M dibuteryl cGMP and 10(-5)M 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.
D000963:Antimetabolites / Q000494:pharmacology; D003078:Colchicine / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D003571:Cytochalasin B / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D006632:Histamine / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008870:Microtubules / Q000187:drug effects; D014176:Protein Biosynthesis; D011691:Puromycin / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000378:metabolism
D000963:Antimetabolites; D003609:Dactinomycin; D003571:Cytochalasin B; D011691:Puromycin; D006632:Histamine; D003513:Cycloheximide; D000242:Cyclic AMP; D006152:Cyclic GMP; D003078:Colchicine