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
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,
References (27)
- et al.
A simple nested RT-PCR method for quantitation of the relative amounts of multiple cytokine mRNAs in small tissue samples
J Immunol Methods
(1996) - et al.
Caspase-1-independent, Fas/Fas ligand-mediated IL-18 secretion from macrophages causes acute liver injury in mice
Immunity
(1999) - et al.
Defective NK cell activity and Th1 response in IL-18-deficient mice
Immunity
(1998) - et al.
Inflammatory microcrystals stimulate interleukin-6 production and secretion by human monocytes and synoviocytes
Arthritis Rheum
(1989) - et al.
Interleukin 1 (IL 1) as a mediator of crystal arthritis. Stimulation of T cell and synovial fibroblast mitogenesis by urate crystal-induced IL 1
J Immunol
(1987) - et al.
Cloning of a new cytokine that induces IFN-gamma production by T cells
Nature
(1995) - et al.
A role for IL-18 in neutrophil activation
J Immunol
(2001) - et al.
Preliminary criteria for the classification of the acute arthritis of primary gout
Arthritis Rheum
(1977) - et al.
Crystal-induced neutrophil activation. IV. Specific inhibition of tyrosine phosphorylation by colchicine
J Clin Invest
(1993) - et al.
The murine homolog of the interleukin-8 receptor CXCR-2 is essential for the occurrence of neutrophilic inflammation in the air pouch model of acute urate crystal-induced gouty synovitis
Arthritis Rheum
(1998)
Pathophysiological roles of interleukin-18 in inflammatory liver diseases
Immunol Rev
Enhancement of human cord blood CD34 cell-derived NK cell cytotoxicity by dendritic cells
J Immunol
Interleukin-18 (interferon-gamma-inducing factor) is produced by osteoblasts and acts via granulocyte/macrophage colony-stimulating factor and not via interferon-gamma to inhibit osteoclast formation
J Exp Med
Cited by (43)
Acute effects of photobiomodulation applied on the dorsal root ganglion in gout model-induced rats
2023, Journal of Photochemistry and Photobiology B: BiologyThe biology of urate
2020, Seminars in Arthritis and RheumatismCitation Excerpt :Local factors may promote nucleation and crystal growth (e.g., low pH, elevated calcium levels, organic molecules originating from cartilage or the synovium, albumin, antibodies, sodium ions) [2,3]. MSU crystals activate a specific inflammatory cascade in leukocytes leading to production of IL-1 and IL-18 [113–117]. The innate immune system recognizes and responds to pathogens and to endogenous molecules released by host cells via detection of pathogen-associated and danger-associated molecular patterns (PAMPS and DAMPs respectively).
The NLRP3 inflammasome - interleukin 1 pathway as a therapeutic target in gout
2019, Archives of Biochemistry and BiophysicsCitation Excerpt :Indeed, IL-1α is also released during MSU-induced inflammation [85,86]. IL-18; a member of the IL-1 family, is also abundantly produced in gout via similar, caspase-1-dependent mechanisms [87]. The activation of the NLRP3 - IL-1 axis leads to the production of several other inflammatory mediators and the perpetuation of the gouty inflammatory cascade.
Efficacy of CoenzymeQ10 in inhibiting monosodium urate crystal-induced inflammation in rats
2016, European Journal of PharmacologyCitation Excerpt :Gouty arthritis is a common hyperuricemic condition caused by formation and deposition of monosodium urate crystals in synovial fluids of joints. It has been reported that during the acute condition of this disease MSU crystals are found inside the leukocytes of synovial fluid (Inokuchi et al., 2006). A small part of these neutrophils phagocytose monosodium urate crystals and discharge certain mediators which amplify inflammation reaction (Landis and Haskard, 2001).