The characteristic function of interleukin (IL)-15 appears to be its ability to mimic the stimulatory action of IL-2 on lymphocytes by utilizing part of the IL-2 receptor complex. To gain insight into the immunoregulatory properties of this cytokine in patients with minimal-change nephrotic syndrome (MCNS), we analyzed effects of IL-15 on vascular permeability factor (VPF) release in vitro. Peripheral blood mononuclear cells (PBMC) were isolated from 16 patients with MCNS, 16 patients with IgA nephropathy (IgAN) and 16 healthy controls. Cells were stimulated with concanavalin A (Con A) and the VPF was assessed using the method of Lagrue with minor modifications. PBMC secreted significantly increased amounts of VPF under stimulation with Con A in patients with MCNS and IgAN patients with the nephrotic syndrome as compared with normal controls. Here we have demonstrated, for the first time, that addition of IL-15 to PBMC obtained from nephrotic patients as well as from normal controls increased Con A-induced release of VPF by 250%. This stimulatory effect was found highly significant and was dose-dependent. The effect of IL-15 on the secretion of VPF was specific, since a complete reversion was obtained with a neutralizing antibody to human IL-15. Our findings reveal that IL-15 has the potential to function as an immunoregulatory molecule of PBMC VPF release. In addition, IL-15 had similar effects to IL-2 in terms of its capacity to upregulate VPF release. Taken together, our data emphasize a positive regulatory role for IL-15 in inducing the release of VPF when present at optimal levels. Therefore, IL-15 antagonists may provide a basis for immune intervention in the pathophysiology of VPF.

Keywords:
Minimal-change nephrotic syndrome, Vascular permeability factor, Interleukin-15, Interleukin-2
1.
Lagrue G, Xheneumont S, Branellec A, Hirbec G, Weil B: Vascular permeability factor elaborated from lymphocytes. I. Demonstration in patients with nephrotic syndrome. Biomedicine 1975;23:37–40.
2.
Sobel AT, Branellec AI, Blanc CJ, Lagrue G: Physicochemical characterization of a vascular permeability factor produced by Con A-stimulated human lymphocytes. J Immunol 1977;119:1230–1234.
3.
Yoshizawa N, Kusumi Y, Matsumoto K, Oshima S, Takeuchi A, Kawamura O, Kubota T, Kondo S, Niwa H: Studies of a glomerular permeability factor in patients with minimal-change nephrotic syndrome. Nephron 1989;51:370–376.
4.
Matsumoto K: Interleukin-10 inhibits vascular permeability factor release by peripheral blood mononuclear cells in patients with lipoid nephrosis. Nephron 1997;75:154–159.
5.
Matsumoto K, Ohi H, Kanmatsuse K: Interleukin-10 and interleukin-13 synergize to inhibit vascular permeability factor release by peripheral blood mononuclear cells from patients with lipoid nephrosis. Nephron 1997;77:212–218.
6.
Matsumoto K, Ohi H, Kanmatsuse K: Interleukin-4 cooperates with interleukin-10 to inhibit vascular permeability factor release by peripheral blood mononuclear cells from patients with minimal-change nephrotic syndrome. Am J Nephrol, in press.
7.
Grabstein KH, Eisenmann J, Shanebeck K, Rauch C, Srinivasan S, Fung V, Beers C, Richardson J, Schoenborn MA, Ahdieh M, Johnson L, Alderson MR, Watson JD, Anderson DM, Giri JG: Cloning of a T cell growth factor that interacts with the β chain of the interleukin-2 receptor. Science 1994;264:965–968.
8.
Carson WE, Giri JG, Lindermann MJ, Linett ML, Ahdieh R, Paxton R, Anderson D, Eisenmann J, Grabstein K, Caliguiri MA: Interleukin (IL) 15 is a novel cytokine that activates human natural killer cells via components of the IL-2 receptor. J Exp Med 1994;180:1395–1403.
9.
Schena FP: A retrospective analysis of the natural history of primary IgA nephropathy world-wide. Am J Med 1990;89:209–215.
10.
Danielpour D, Roberts AB: Specific and sensitive quantitation of transforming growth factor β3 by sandwich enzyme linked immunosorbent assay. J Immunol Methods 1995;180:265–272.
11.
Alleva DG, Kaser SB, Monroy MA, Fenton MJ, Beller DI: IL-15 functions as a potent autocrine regulator of macrophage proinflammatory cytokine production. Evidence for differential receptor subunit utilization associated with stimulation or inhibition. J Immunol 1997;159:2941–2951.
12.
Matsumoto K, Ohi H, Kanmatsuse K: Interleukin-12 upregulates the release of vascular permeability factor by peripheral blood mononuclear cells from patients with lipoid nephrosis. Nephron 1998;78:403–409.
13.
Hsieh C-S, Macatonia SE, Tripp CS, Wolf ST, O’Garra A, Murphy KM: Development of Th1 CD4+ T cell through IL-12 produced by Listeria-induced macrophages. Science 1993;260:547–549.
14.
McCarthy ET, Sharma R, Sharma M, Li J-Z, Ge X-L, Dileepan KN, Savin VJ: TNF-α increases albumin permeability of isolated rat glomeruli through the generation of superoxide. J Am Soc Nephrol 1998;9:433–438.
15.
Savin VJ, Sharma R, Sharma M, McCarthy ET, Swan SK, Ellis E, Lovell H, Warady B, Gunwar S, Chonko AM, Artero M, Vincenti E: Circulating factor associated with increased glomerular permeability to albumin in recurrent focal segmental glomerulosclerosis. N Engl J Med 1996;334:878–883.
16.
Matsumoto K: Decreased release of IL-10 by monocytes from patients with lipoid nephrosis. Clin Exp Immunol 1995;102:603–607.
1999
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