Background/Purpose: Adult-onset Still’s disease (AOSD) is a systemic inflammatory disease, the cause of which is largely unknown. AOSD has been recently classified as one of the autoinflammatory diseases in which innate rather than acquired immunity plays an important role in the pathogenesis. Serum IL-18 has been shown to be high in AOSD patients. In this study, we first quantified the levels of multiple cytokines in the serum of AOSD patients and then compared the cytokine profile with that of healthy controls. We next evaluated the effects of the cytokines detectable in the AOSD serum on natural killer (NK) cells, since NK cells are cells of innate immunity and IL-18 has been shown to enhance their cytotoxicity.

Methods: Our patients fulfilled Yamaguchi’s criteria for the diagnosis of AOSD. We quantified the serum levels of 10 cytokines (IFN-α, IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12p70, IL-17A and TNF-α) using multiplex bead array assays and IL-18 using ELISA. We next sorted NK cells from peripheral blood mononuclear cells of healthy controls and stimulated them in vitro in the presence of cytokines that were detected in the AOSD serum. We quantified the level of IFN-γ in the culture supernatant by ELISA and assessed the surface expression level of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on NK cells by flow cytometry.

Results: The level of IL-18 was high in all of the AOSD samples. IL-6 was detectable in 8 out of 16 patients and IL-10 in 3 out of 16. In contrast, serum IFN-γ was not detected in any sample. When NK cells were stimulated in vitro with IL-18 alone, IFN-γ was undetectable in the culture supernatant. The combination of IL-10 and IL-18, but not IL-6 and IL-18, induced IFN-γ. We evaluated the expression of the receptors for IL-6 and IL-10 on NK cells and found that IL-10R and IL-10RB were present, while IL-6R and gp130 were absent. The combination of IL-10 and IL-18 also induced TRAIL expression on NK cells.

Conclusion: Since IL-18 was originally identified as an inducer of IFN-γ, it was surprising that IFN-γ was not detected in the serum despite the high level of IL-18. Indeed, IL-18 alone did not induce the production of IFN-γ from NK cells in vitro. The combination of IL-10 and IL-18, but not IL-6 and IL-18, induced the production of IFN-γ and surface expression of TRAIL on NK cells. As IL-6 is a classic pro-inflammatory cytokine and IL-10 is considered anti-inflammatory, this result was also rather unexpected. The unresponsiveness to IL-6 may be explained by the absence of IL-6 receptor on NK cells. Locally-produced IFN-γ can be detrimental to the body by activating macrophages. As the liver is rich in NK cells and TRAIL has been reported to cause liver injury, TRAIL on NK cells may be responsible for one of the characteristics of AOSD, liver dysfunction. Although IL-10 may be produced to prevent excessive inflammation, in the presence of IL-18, it can exert the opposite effect.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/in-the-presence-of-il-18-il-10-but-not-il-6-induces-ifn-%ce%b3-production-and-the-surface-expression-of-trail-on-nk-cells/