3-deaza-adenosine inhibition of stimulus-response coupling in human polymorphonuclear leukocytes.
In an effort to define better the functional role of S-adenosyl-methionine-mediated methylation reactions in modulating polymorphonuclear (PMN) functional responses to chemotactic stimuli, we investigated the effects of 3-deaza-adenosine (3-DZA), a known inhibitor of methylation reactions in phagocytic cells, on formyl methionyl-leucyl-phenylalanine (FMLP)-induced responses in human PMN leukocytes. Using the fluorescent cyanine dye 3,3'-dipropylthiocarbocyanine (di-S-C3-(5)) as an optical probe of membrane potential we observed that 3-DZA at concentrations that inhibit FMLP-induced O2- production does not significantly alter FMLP-induced changes in transmembrane potential. Additional studies showed an inhibitory effect of 3-DZA on FMLP-induced PMN pinocytosis and to a lesser degree on FMLP-induced degranulation. However, pretreatment of PMNs with 3-DZA did not alter FMLP-induced changes in Quin-2 fluorescence, an indicator of changes in intracellular calcium levels. These findings demonstrate a dissociation between chemotactic factor-induced cell membrane depolarization, changes in intracellular calcium, and specific neutrophil functional responses and suggest that chemotactic factor-induced changes in transmembrane potential and intracellular calcium are independent of chemotactic factor-induced methylation reactions. Furthermore, 3-DZA did not alter phorbol myristate acetate induced O2- production or fluid pinocytosis indicating a stimulus specificity for the inhibitory effects of this agent on O2- production.
Fantone
J C
JC
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109.
Duque
R E
RE
Davis
B H
BH
Phan
S H
SH
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D008745:Methylation; D009240:N-Formylmethionine Leucyl-Phenylalanine; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D010873:Pinocytosis / Q000187:drug effects; D013481:Superoxides / Q000096:biosynthesis; D014372:Tubercidin / Q000494:pharmacology*
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D007166:Immunosuppressive Agents; C018258:3-deazaadenosine; D013481:Superoxides; D009240:N-Formylmethionine Leucyl-Phenylalanine; D000242:Cyclic AMP; D014372:Tubercidin; D002118:Calcium