Background/Aim: In a previous study, we reported that interleukin (IL)-12 could upregulate the production of vascular permeability factor (VPF) derived from activated human peripheral blood mononuclear cells. Since IL-18, a novel immunoregulatory cytokine with potent interferon-γ inducing activities, has been shown to be a strong cofactor for T helper type 1 cell development, we tested the hypothesis that IL-18 in combination with IL-12 can act synergistically to modulate the production of VPF. Methods: For this purpose, T cells were isolated from heparinized venous blood, stimulated with concanavalin A, and incubated in the presence of IL-18 or IL-12, and the production of VPF was determined by the method of Lagrue. Results: There was a significant increase in VPF production from concanavalin A-stimulated T cells following incubation with IL-18 or IL-12. More importantly, the combination of the cytokines was found to give a potent synergistic stimulation of VPF by concanavalin A-activated T cells from normal subjects. To determine the specificity of the stimulatory effect, neutralizing anti-IL-18 and anti-IL-12 antibodies were preincubated with IL- 18 and IL-12, respectively, prior to the addition of responder cells. The antibodies completely inhibited the effects of IL-18 and IL-12. Thus, these data show that IL-18 can synergize with IL-12 to selectively increase the production of VPF from T cells. The present study further demonstrates that IL-18 and IL-12 are in fact acting in synergy in patients with minimal-change nephrotic syndrome. Conclusions: Taken together, our results indicate that both IL-18 and IL-12 contribute to the VPF production in vitro and suggest that they play key roles in the complexity of cytokine regulation in the pathophysiology of VPF.

Keywords:
T cells, Vascular permeability factor, Interleukin-18, Interleukin-12, Minimal-change nephrotic syndrome
1.
Lagrue G, Xheneumont S, Branellec A, Hirbec G, Weil B: A vascular permeability factor elaborated from lymphocytes. I. Demonstration in patients with nephrotic syndrome. Biomedicine 1975;23:37–40.
2.
Heslan J-MJ, Branellec A, Pilatte Y, Lang P, Lagrue G: Differentiation between vascular permeability factor and IL-2 in lymphocyte supernatants from patients with minimal-change nephrotic syndrome. Clin Exp Immunol 1991;86:157–162.
3.
Yoshizawa N, Kusumi Y, Matsumoto K, Ohshima 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.
Boulton-Jones JM, Tulloch I, Dore B, McLay A: Changes in the glomerular capillary wall induced by lymphocyte products and serum of nephrotic patients. Clin Nephrol 1983;20:72–77.
5.
Matsumoto K, Kanmatsuse K: Increased IL-12 release by monocytes in nephrotic patients. Clin Exp Immunol 1999;117:361–367.
6.
Yoshimoto T, Takeda K, Tanaka T, Ohkusu K, Kashiwamura S, Okamura H, Akira S, Nakanishi K: IL-12 up-regulates IL-18 receptor expression on T cells, Th1 cells, and B cells: Synergism with IL-18 for IFN-γ production. J Immunol 1998;161:3400–3407.
7.
Matsumoto K, Ohi H, Kanmatsuse K: Interleukin-12 up-regulates the release of vascular permeability factor by peripheral blood mononuclear cells from patients with lipoid nephrosis. Nephron 1998;78:403–409.
8.
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 1999;19:21–27.
9.
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.
10.
Okamura H, Tsutsui H, Komatsu T, Yutsudo M, Hakura A, Tanimoto T, Torigoe K, Okura T, Nukada Y, Hattori K: Cloning of a new cytokine that induces IFN-γ production by T cells. Nature 1995;378:88–91.
11.
Kohno K, Kataoka J, Ohtsuki T, Suemoto Y, Okamoto I, Usui M, Ikeda M, Kurimoto M: IFN-γ-inducing factor (IGIF) is a costimulatory factor on the activation of Th1 but not Th2 cells and exerts its effect independently of IL-12. J Immunol 1997;158:1541–1550.
12.
Daniel V, Trautmann Y, Konrad M, Nayir A, Schräder K: T-lymphocyte populations, cytokines and other growth factors in serum and urine of children with idiopathic nephrotic syndrome. Clin Nephrol 1997;47:289–297.
13.
Schmitt E, Hoehn P, Huels C, Goedert S, Palm N, Rüde E, Germann T: T helper type 1 development of naive CD4+ T cells requires the coordinate action of interleukin-12 and interferon-γ and is inhibited by transforming growth factor-β. Eur J Immunol 1994;24:793–798.
© 2000 S. Karger AG, Basel
2000
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.