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The effect of pentoxifylline on human neutrophil migration: a possible role for cyclic nucleotides
J G Elferink1, T W Huizinga, B M de Koster
1Department of Medical Biochemistry, Leiden University, The Netherlands.
Abstract:
Relatively low concentrations of pentoxifylline caused a stimulation of random migration, while high concentrations inhibited chemotactic migration activated by formyl-methionyl-leucyl-phenylalanine (fMLP). The stimulating effect of pentoxyfylline was partly chemokinetic and partly chemotactic, and was dependent on extracellular calcium. Activation of migration by pentoxifylline was not dependent on the pore size of the micropore filter, indicating that the effect was not mediated by the ability of the drug to induce membrane deformability. Inhibitors of guanylate cyclase and antagonists of cGMP-dependent protein kinase (G-kinase) inhibited stimulation of migration by pentoxifylline. Pentoxyfylline caused a transient increase in cGMP level, while only high concentrations of pentoxifylline caused an increase in cyclic adenosine monophosphate (cAMP) level. It is suggested that the increase of migration is caused by cGMP and is mediated by a G-kinase, while the inhibition of migration at high concentrations of pentoxifylline is mediated by cAMP.
Insights
Pentoxifylline at low doses stimulates immune cell migration via cyclic GMP (cGMP), while high doses inhibit it through cyclic adenosine monophosphate (cAMP). This suggests distinct cellular mechanisms for pentoxifylline
Area of Science:
- Immunology
- Pharmacology
- Cell Biology
Background:
- Pentoxifylline is a rheologic agent with known immunomodulatory effects.
- Understanding its precise mechanisms on immune cell migration is crucial for therapeutic applications.
Purpose of the Study:
- To elucidate the concentration-dependent effects of pentoxifylline on immune cell migration.
- To investigate the intracellular signaling pathways involved in pentoxifylline-mediated migration.
Main Methods:
- Assessing random and chemotactic migration of immune cells using micropore filters.
- Evaluating the role of extracellular calcium, guanylate cyclase, and protein kinase G (G-kinase).
- Measuring intracellular levels of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP).
Main Results:
- Low pentoxifylline concentrations stimulated migration, partly chemokinetic and chemotactic, dependent on extracellular calcium.
- High concentrations of pentoxifylline inhibited formyl-methionyl-leucyl-phenylalanine (fMLP)-induced chemotactic migration.
- Pentoxifylline induced a transient increase in cGMP, while high concentrations also increased cAMP; inhibition was linked to cAMP, and stimulation to cGMP/G-kinase.
Conclusions:
- Pentoxifylline exhibits dual effects on immune cell migration, concentration-dependently.
- cGMP and G-kinase mediate the stimulatory effects of pentoxifylline.
- cAMP pathways are implicated in the inhibitory effects of high-dose pentoxifylline on immune cell migration.