Soluble cytokine receptors as carrier proteins: effects of soluble interleukin-4 receptors on the pharmacokinetics of murine interleukin-4.
Soluble interleukin-4 (IL-4) receptors (sIL-4R) can have either enhancing or inhibitory effects on the activity of IL-4 in vivo, depending on the relative concentration ratios of sIL-4R to IL-4. Whereas competition with membrane IL-4 receptors is the basis for their inhibitory action, the mechanisms responsible for the potentiation of IL-4 activity are not completely clear but may involve alterations in the half-life and biodistribution of IL-4 in vivo. To better understand the basis for the enhancing effect of sIL-4R, we have analyzed their effects on the pharmacokinetic properties of IL-4. Studies with radiolabeled recombinant IL-4 demonstrated that, when injected alone, IL-4 was rapidly cleared from the circulation and eliminated through the kidneys in a proteolytically degraded form. Administration of IL-4 in combination with increasing concentrations of sIL-4R resulted in a dose-dependent enhancement in the blood levels of IL-4 and a concomitant reduction in its clearance from circulation and excretion in the urine. Differences between measurements of IL-4 concentrations based on radioactivity and enzyme-linked immunosorbent assays indicated that the injected IL-4 was rapidly inactivated in vivo and that the presence of sIL-4R diminished this process. The inactivation of IL-4 was mediated through the membrane IL-4 receptors and required receptor internalization and intact lysosomal function. Taken together, these results suggest that sIL-4R are able to alter the pharmacokinetic properties of IL-4, prolonging its half-life in the circulation and reducing its clearance through diminished renal excretion and/or interference with inactivation. These effects are consistent with the ability of sIL-4R to potentiate IL-4 activity in vivo.
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Department of Microbiology and immunology, School of Medicine, University of Louisville, Kentucky, USA.
Hurst
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Fernandez-Botran
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D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002850:Chromatography, Gel; D004337:Drug Carriers; D007167:Immunotherapy; D015847:Interleukin-4 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018123:Receptors, Interleukin / Q000378:metabolism*; D019948:Receptors, Interleukin-4; D011994:Recombinant Proteins / Q000494:pharmacology; D014018:Tissue Distribution
D015703:Antigens, CD; D002352:Carrier Proteins; D004337:Drug Carriers; D018123:Receptors, Interleukin; D019948:Receptors, Interleukin-4; D011994:Recombinant Proteins; D015847:Interleukin-4