Surfactant protein A (SP-A)-tacrolimus complexes have a greater anti-inflammatory effect than either SP-A or tacrolimus alone on human macrophage-like U937 cells
SP-A binds to FK506 with high affinity and strengthens tacrolimus potency as an anti-inflammatory agent on macrophages by facilitating FK506 entrance into the cell, overcoming P-glycoprotein. Intratracheal administration of immunosuppressive agents to the lung is a novel treatment after lung transpl...
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Veröffentlicht in: | European journal of pharmaceutics and biopharmaceutics 2011-04, Vol.77 (3), p.384-391 |
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Sprache: | eng |
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Zusammenfassung: | SP-A binds to FK506 with high affinity and strengthens tacrolimus potency as an anti-inflammatory agent on macrophages by facilitating FK506 entrance into the cell, overcoming P-glycoprotein.
Intratracheal administration of immunosuppressive agents to the lung is a novel treatment after lung transplantation. Nanoparticles of tacrolimus (FK506) might interact with human SP-A, which is the most abundant lipoprotein in the alveolar fluid. This study was undertaken to determine whether the formation of FK506/SP-A complexes interferes with FK506 immunosuppressive actions on stimulated human macrophage-like U937 cells. We found that SP-A was avidly bound to FK506 (Kd=35±4nM), as determined by solid phase–binding assays and dynamic light scattering. Free FK506, at concentrations ⩽1μM, had no effect on the inflammatory response of LPS-stimulated U937 macrophages. However, coincubation of FK506 and SP-A, at concentrations where each component alone did not affect LPS-stimulated macrophage response, significantly inhibited LPS-induced NF-κB activation and TNF-alpha secretion. Free FK506, but not FK506/SP-A, functioned as substrate for the efflux transporter P-glycoprotein. FK506 bound to SP-A was delivered to macrophages by endocytosis, since several endocytosis inhibitors blocked FK506/SP-A anti-inflammatory effects. This process depended partly on SP-A binding to its receptor, SP-R210. These results indicate that FK506/SP-A complexes have a greater anti-inflammatory effect than either FK506 or SP-A alone and suggest that SP-A strengthened FK506 anti-inflammatory activity by facilitating FK506 entrance into the cell, overcoming P-glycoprotein. |
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ISSN: | 0939-6411 1873-3441 |
DOI: | 10.1016/j.ejpb.2010.12.013 |