THU0050 IMPLICATIONS OF THE DIFFERENT RESPONSES OF NK CELLS AND MONOCYTES TO IL-6 AND IL-10 IN THE PATHOGENESIS OF ADULT-ONSET STILL’S DISEASE
Authors: Kojiro Sato, Yoshimi Aizaki, Hiroaki Yazawa, Toshihide Mimura
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Adult-onset Still's disease (AOSD) is a systemic inflammatory disease, the cause of which is largely unknown. AOSD has recently been 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 highly elevated in AOSD patients [1,2]. <h3>Objectives:</h3> We attempted to quantify the levels of multiple cytokines in the serum of AOSD patients and to evaluate the effects of the cytokines detectable in the AOSD serum on natural killer (NK) cells and monocytes, since these are cells critical to innate immunity. <h3>Methods:</h3> 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 or monocytes from peripheral blood mononuclear cells of healthy controls and stimulated each of the cell populations <i>in vitro</i> in the presence of the cytokines that had been 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. Intracellular staining of proinflammatory cytokines in monocytes was performed after stimulation with the same combinations of cytokines. <h3>Results:</h3> The level of IL-18 was high in all of the AOSD samples tested. 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 of the samples. When NK cells were stimulated <i>in vitro</i> 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-10Rβ were present, while IL-6R and gp130 were absent. The combination of IL-10 and IL-18 also induced TRAIL expression on NK cells in an IFN-γ-independent manner. In contrast, monocytes expressed both the IL-6 and IL-10 receptors. Monocytes stimulated with IL-6 expressed IL-1β and those stimulated with IL-18 expressed IL-6; L-10 exhibited inhibitory rather than stimulatory effects on monocytes. <h3>Conclusion:</h3> IL-18 alone did not induce the production of IFN-γ from NK cells <i>in vitro</i>. The combination of IL-10 and IL-18, but not IL-6 and IL-18, induced the production of IFN-γ and the surface expression of TRAIL on NK cells. In contrast, monocytes did express IL-6 receptors, and when stimulated with IL-6 or IL-18, produced various inflammatory cytokines, which were inhibited, not stimulated, in the presence of IL-10. Thus, the same cytokines can exert very different effects on inflammation, which is partly explained by the specific expression of corresponding receptors. <h3>References:</h3> [1]Kawashima M,&nbsp;et al.,&nbsp;Arthritis Rheum.&nbsp;2001;44(3):550-60. [2]Yoshida Y, et al., Intern Med. 2011;50(16):1757-60. <h3>Disclosure of Interests:</h3> None declared