Menachem Rubinstein

Interleukin-18, interleukin-18 binding protein and impaired production of interferon-gamma in chronic renal failure.

UNLABELLED Uremia is associated with suppressed cellular immune responses, manifested, in part, by impaired interferon-gamma (IFNgamma) production. We investigated the influence of kidney function on plasma levels of interleukin-18 binding protein (IL-18BP), the naturally occurring inhibitor of IL-18. METHODS Plasma levels of IL-18, IL-18BP and IFNgamma were measured by specific immunoassays in patients with normal kidney function (NKF, n = 29), in patients with chronic renal insufficiency (CRI, n = 29), and in patients on hemodialysis (HD, n = 40). In addition, Staphylococcus epidermidis-induced production of IFNgamma and IL-18 in whole blood cultures was determined in 12 patients on HD and compared to production in 9 controls with NKF. RESULTS Plasma IL-18 (mean +/- SEM) in NKF was 17.9 +/- 3.6 pg/ml, in CR142.6 +/- 7.0 pg/ml (p < 0.01), and in HD 93.5 +/- 13.6 pg/ml (p < 0.001). The level of IL-18BP in NKF was 3.4 +/- 0.4 ng/ml, in CRI 7.5 +/- 0.7 ng/ml (p < 0.001), and in HD 13.1 +/- 0.8 ng/ml (p < 0.001). Plasma IL-18BP was inversely correlated with creatinine clearance (correlation coefficient: -0.7479). The level of free IL-18 was calculated in NKF to be 13.8 +/- 3.3 pg/ml, in CRI 23.6 +/- 3.9 pg/ml (not significant), and in HD 39.6 +/- 5.9 pg/ml (p < 0.001). Stimulated whole blood production of IFNgamma in NKF was 185 +/- 74 pg/10(6) mononuclear cells (PBMC), but suppressed in HD to 27.3 +/- 16 pg/10(6) PBMC (p < 0.05). CONCLUSION In uremia, retention of IL-18BP does not suffice to neutralize most of the concomitantly raised levels of total IL-18 resulting in elevated levels of free IL-18. Nevertheless, IFNgamma production in whole blood is reduced in patients on HD. Therefore, suppression of IFNgamma production in uremia may be due to inhibitors of IFNgamma production other than IL-18BP.

Purification of the Human Interferon-γ Receptor by Ligand Affinity

Interferon-γ(IFN-γ) is a product of activated T lymphocytes (Kasahara et al., 1983) and low density lymphocytes (Fischer and Rubinstein, 1983). In addition to its antiviral and growth inhibitory activities, IFN-γis one of the major immunoregulatory lymphokines. Its immunoregulatory functions include macrophage activation, growth, differentiation, and maturation of various immunocytes and induction of class I and II MHC gene products both in macrophages and in cells of nonhematopoietic origin (for a review see Trinchieri and Perrusia, 1985). A survey of its various activities reveals that IFN-γelicits 50% of its maximal effect at concentrations of 0.5-1 pM. Indeed, the level of IFN-γ in blood or in other tissue fluids rarely exceeds the lower limit of detection, which is about 10 antiviral U/mL (10 pM). Therefore, a highly sensitive and selective system must be present in the cells in order to trace IFN-γ and respond to it. Such a system is the cell surface receptor. In this respect, IFN-γ is similar to other polypeptide hormones, lymphokines, and other cytokines, all acting through specific cell-membrane receptors. This array of polypeptides and their receptors serve as an efficient chemical signaling network that is essential for the existence of multicellular organisms.