REGULATION OF CIPROFLOXACIN UPTAKE IN HUMAN PROMYELOCYTIC LEUKEMIA-CELLS AND POLYMORPHONUCLEAR LEUKOCYTES

Polymorphonuclear leukocytes (PMNs) actively internalize ciprofloxacin , a capability that can enhance killing of intracellular bacteria and facilitate delivery of the antimicrobial agent to infection sites by m igrating PMNs, In this study we investigated mechanisms for up-regulat ion of this process, Activation with N-formyl-methionyl-leucyl-phenyla lanine (fMLP; 100 nM) enhanced PMN ciprofloxacin uptake by 50% (P < 0. 05), Phorbol myristate acetate (PMA; greater than or equal to 10 nM) e nhanced uptake by at least 36-fold, mainly by stimulating an increase in the V-max of the ciprofloxacin transporter, This effect of PMA was inhibited by antagonists of protein kinase C (H7 and chelerythrine) an d the mitogen-activated protein kinase cascade downstream (PD 098059), Under resting and PMA-activated conditions, ciprofloxacin uptake by i mmature human promyelocytic leukemia (HL-60) cells was much lower than in PMNs, However, when HL-60 cells were induced to mature into PMN-li ke cells, their ciprofloxacin uptake activity increased markedly, Thes e findings implicate a role for protein kinase C in up-regulation of t he ciprofloxacin transporter and suggest that myeloid cells acquire an enhanced ability to take up ciprofloxacin as they mature to end-stage .