Interleukin-18 and interleukin-12 synergize to stimulate the production of vascular permeability factor by T lymphocytes in normal subjects and in patients with minimal-change nephrotic syndrome.
OBJECTIVE
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-gamma 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.
Matsumoto
K
K
Department of Medical Technology, College of Medical Sciences, Saitama Prefectural University, Koshigaya, Japan.
Kanmatsuse
K
K
D000328:Adult; D016022:Case-Control Studies; D003208:Concanavalin A / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D016228:Endothelial Growth Factors / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D018664:Interleukin-12 / Q000008:administration & dosage*; D020382:Interleukin-18 / Q000008:administration & dosage*; D007700:Kinetics; D008222:Lymphokines / Q000096:biosynthesis*; D008297:Male; D009402:Nephrosis, Lipoid / Q000209:etiology* / Q000276:immunology / Q000503:physiopathology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D020382:Interleukin-18; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D003208:Concanavalin A; D018664:Interleukin-12