FK506 suppresses neutrophil chemoattractant production by peripheral blood mononuclear cells
Introduction
FK506 (Tacrolimus) is a 23-membered macrolide immunosuppressant isolated from Streptomyces tsukubaensis (Kino et al., 1987a). Its immunosuppressive mechanism involves inhibition of calcineurin by a complex of FK506 and a 12-kDa immunophilin FKBP12, resulting in an inability to assemble the active form of the transcription factor NF-AT and subsequent down-regulation of several cells, especially T lymphocyte cytokine transcription Jain et al., 1993, Liu et al., 1991, Kino et al., 1987b. FK506 also inhibits degranulation from mast cells, basophils and neutrophils De Paulis et al., 1992, Forrest et al., 1991. However, the effect of FK506 on neutrophil chemotaxis has not been fully determined.
Human neutrophils play a major role in the host defense response against bacterial infection (Babior, 1978) and in the pathogenesis of various inflammatory diseases such as rheumatoid arthritis, psoriasis and asthma Brennan et al., 1990, Biasi et al., 1998, Frangova et al., 1996. Since neutrophil chemotaxis is an early and important step in the inflammation process, the suppression of neutrophil chemotaxis should be of a great therapeutic value for such diseases. FK506 suppresses neutrophil migration to human kidney graft after transplantation and rat liver in an ischemia–reperfusion model, but the exact mechanism remains unknown Woodle et al., 1997, Garcia-Criado et al., 1997. Although it has been reported that FK506 suppresses neutrophil chemotaxis induced by formyl-Met–Leu–Phe (fMLP) or FKBP Burnett et al., 1994, Leiva and Lyttle, 1992, the effect of FK506 on neutrophil chemotaxis induced by another chemoattractant has not been reported.
To understand the mechanism of action of FK506 on neutrophil chemotaxis, we examined its direct effect on human neutrophil chemotaxis induced by various chemoattractants. We also examined whether FK506 can suppress neutrophil chemotaxis by inhibiting cytokine production by peripheral blood mononuclear cells.
Section snippets
Reagents
Recombinant human interleukin-8 (R&D systems), leukotriene B4 (CASCADE), platelet-activating factor (PAF, Sigma), complement 5a (C5a, Sigma) and fMLP (Sigma) were purchased. Zymosan-activated serum was prepared by stimulating human peripheral blood serum with zymosan A (Sigma). The minimum concentrations of these chemoattractant, at which the maximum chemoattractive activities for human neutrophils were obtained, were determined in a series of preliminary experiments (data not shown).
Direct effects of FK506, cyclosporin A and dexamethasone on human neutrophil chemotaxis induced by various chemoattractants
The direct effects of FK506, cyclosporin A and dexamethasone on human neutrophil chemotaxis induced by several chemoattractants, recombinant human interleukin-8, leukotriene B4, PAF, C5a, zymosan-activated serum and fMLP, were examined. Except for PAF, no significant suppression by FK506 or cyclosporin A was observed on chemoattractant-induced chemotactic activity in concentrations up to 1 μg/ml (Table 1). Only in the case of the chemotactic activity induced by PAF did FK506 show slight
Discussion
In this study, we initially examined the direct effect of FK506 on human neutrophil chemotaxis induced by the chemoattractants, recombinant human interleukin-8, leukotriene B4, PAF, C5a, zymosan-activated serum and fMLP. The effects of two other well known immunosuppressive agents, cyclosporin A and dexamethasone, were also examined in a similar manner. Except for PAF, no significant suppressive effects of FK506 or cyclosporin A were observed. Only in the case of the chemotactic activity
Acknowledgements
We thank Dr. David Barrett, Medicinal Chemistry Research Laboratories, for a critical reading of the manuscript.
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