Regulation of ciprofloxacin uptake in human promyelocytic leukemia cells and polymorphonuclear leukocytes

J Leukoc Biol. 1997 May;61(5):619-23. doi: 10.1002/jlb.61.5.619.

Abstract

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 migrating PMNs. In this study we investigated mechanisms for up-regulation of this process. Activation with N-formyl-methionyl-leucyl-phenylalanine (fMLP; 100 nM) enhanced PMN ciprofloxacin uptake by 50% (P < 0.05). Phorbol myristate acetate (PMA; > or = 10 nM) enhanced uptake by at least 36-fold, mainly by stimulating an increase in the Vmax of the ciprofloxacin transporter. This effect of PMA was inhibited by antagonists of protein kinase C (H7 and chelerythrine) and the mitogen-activated protein kinase cascade downstream (PD 098059). Under resting and PMA-activated conditions, ciprofloxacin uptake by immature human promyelocytic leukemia (HL-60) cells was much lower than in PMNs. However, when HL-60 cells were induced to mature into PMN-like cells, their ciprofloxacin uptake activity increased markedly. These findings implicate a role for protein kinase C in up-regulation of the ciprofloxacin transporter and suggest that myeloid cells acquire an enhanced ability to take up ciprofloxacin as they mature to end-stage PMNs.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Anti-Infective Agents / blood
  • Anti-Infective Agents / pharmacokinetics*
  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cells, Cultured
  • Ciprofloxacin / blood
  • Ciprofloxacin / pharmacokinetics*
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / pharmacology
  • HL-60 Cells / enzymology
  • HL-60 Cells / metabolism*
  • Humans
  • N-Formylmethionine Leucyl-Phenylalanine / pharmacology
  • Neutrophil Activation / drug effects
  • Neutrophils / enzymology
  • Neutrophils / metabolism*
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / metabolism

Substances

  • Anti-Infective Agents
  • Enzyme Inhibitors
  • Flavonoids
  • N-Formylmethionine Leucyl-Phenylalanine
  • Ciprofloxacin
  • Protein Kinase C
  • Calcium-Calmodulin-Dependent Protein Kinases
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one