Elsevier

Cytokine

Volume 33, Issue 1, 7 January 2006, Pages 21-27
Cytokine

Plasma interleukin (IL)-18 (interferon-γ-inducing factor) and other inflammatory cytokines in patients with gouty arthritis and monosodium urate monohydrate crystal-induced secretion of IL-18

https://doi.org/10.1016/j.cyto.2005.11.010Get rights and content

Abstract

To determine whether levels of interleukin (IL)-18, together with those of IL-1β, tumor necrosis factor-α, IL-6, and IL-8, are elevated in the plasma of patients with gouty arthritis, the plasma concentrations of those cytokines were measured in 31 males with gouty arthritis. Further, CD14+ cells were obtained from human blood and thioglycolate medium-induced peritoneal cells obtained from caspase 1-deficient mice, and then separately cultured in the presence of monosodium urate monohydrate (MSU) crystals. In addition, in an animal in vivo experiment, MSU crystals were injected into subcutaneous air pouches of IL-18-deficient mice. The plasma concentrations of IL-18, IL-6, and IL-8 were elevated in the presence of gouty arthritis in the gout patients. In the in vitro study, the presence of MSU crystals stimulated CD14+ cells (monocytes) to secrete IL-18 and increased the activity of caspase 1 in CD14+ cells, whereas there was no significant effect on IL-18 messenger RNA in CD14+ cells and only a slight induction of IL-18 secretion from thioglycolate medium-induced caspase 1-deficient peritoneal cells. In the in vivo experiment, MSU crystals injected into the air pouch promoted neutrophil accumulation along with an increase in concentrations of keratinocyte-derived chemokine (KC) and macrophage inflammatory protein (MIP)-1α in air-pouch fluids in both IL-18-deficient and wild-type mice. However, there was no increase in the concentration of IL-18 in air-pouch fluids in either mouse strain. Our results suggest that plasma IL-18, IL-6, IL-8, and C-reactive protein (CRP) levels reflect local inflammation associated with gouty arthritis, though IL-18 does not play an important role in neutrophil accumulation. Further, they suggest that MSU crystals accelerate the processing of IL-18 from an inactive to active form via the activation of caspase 1.

Introduction

Gout is a disease that is manifested by an increase in serum urate concentration, recurrent attacks of acute arthritis, deposits of monosodium urate monohydrate (MSU) in and around the joints of the extremities, renal disease involving the interstitial tissues and blood vessels, and uric acid nephrolithiasis. During attacks of acute arthritis, MSU crystals are found in leukocytes in synovial fluids, indicating that they are involved with induction of those attacks. In previous studies [1], [2], MSU crystals were demonstrated to stimulate synovial cells, monocytes-macrophages, and neutrophils to produce a variety of different cytokines including tumor necrosis factor (TNF-)-α, interleukin (IL)-8, IL-1β, IL-6, and monocyte chemotactic factor, which induce acute inflammation. Among them, TNF-α, IL-8, IL-1β and IL-6 are produced by activated macrophages. Okamura et al. reported that the cytokine IL-18 induces the production of interferon-γ from activated Th 1 cells, especially in the presence of IL-12 [3]. Thereafter, IL-18 was demonstrated to be one of the major products of monocytes-macrophages and similarly induced in a number of infectious diseases. In addition, it was recently shown that IL-18 promotes neutrophil accumulation [4].

Since MSU crystals may stimulate macrophages, we hypothesized that they also stimulate synovial membranes and monocyte-macrophages to secrete IL-18 in the joints and that IL-18 play a role in gouty arthritis along with other cytokines. However, there is no known study that has demonstrated that MSU crystals stimulate monocytes-macrophages to produce IL-18. Therefore, we measured plasma IL-18 levels together with those of IL-1β, TNF-α, IL-6, and IL-8 to determine if they are elevated in patients with MSU crystal-induced acute arthritis. Further, in an in vitro study to investigate the mechanism of urate crystal-induced production of IL-18, we determined whether MSU crystals induce human monocytes to produce IL-18 and stimulate Brewer's thioglycolate medium-induced macrophage to produce IL-18 in caspase 1-deficient mice. We also examined whether IL-18 plays a role in MSU crystal-induced neutrophil accumulation in IL-18-deficient mice, since IL-18 is known to promote neutrophil accumulation [4].

Section snippets

Subjects

A total of 31 male outpatients (aged 32–55 years old, mean 45 ± 12 years) with primary gout, diagnosed according to the criteria outlined by the American Rheumatism Association [5], were included in the present study. We did not determine whether MSU crystals were present in the inflamed joints in any of the subjects at the beginning of the study. All of those who are free of gouty arthritis had normal values in routine laboratory tests, which included AST, ALT, serum creatinine, and fasting blood

Plasma CRP, IL-18, IL-1β, TNF-α, IL-6, and IL-8 levels in patients with gout

Plasma C-reactive protein (CRP) was higher in the presence of gouty arthritis than in its absence (P < 0.05) (Table 1). In the 8 patients from whom blood samples were obtained in both the presence and absence of gouty arthritis, plasma CRP was also higher in the presence of gouty arthritis (26 mg/l, range 4–69 mg/l vs. below 3 mg/l, range <3 mg/l) (P < 0.05). However, in the presence of gouty arthritis (n = 16), the level of plasma CRP was not significantly correlated with the level of plasma IL-18 (data

Discussion

IL-18 is a member of the interleukin-1 cytokine superfamily and is recognized as an important regulator of both innate and acquired immunity. It is produced in an inactive 24 kDa precursor form, which is cleaved by IL-1β converting enzyme (caspase 1) and proteinase 3 to generate a biologically active 18 kDa mature form. The active form of IL-18 is secreted by monocytes–macrophages, dendritic cells, and Kupffer cells, as well as some osteoblasts and keratinocytes [11], [12], [13], [14]. Further,

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