Inhibition of natural killer (nk) cell cytotoxicity by interleukin-6: implications for the pathogenesis of macrophage activation syndrome

Abstract

ABSTRACT Objective. Systemic juvenile idiopathic arthritis (s-JIA) is associated with high levels of Interleukin-6 (IL-6) in serum and in synovial fluid. Also, impairment of natural killer (NK) cell function is often observed. Our aim was to evaluate a possible link between these two biological findings, as well as with the development of macrophage activation syndrome (MAS), a condition frequently observed in s-JIA. Methods. Splenic NK-cell cytotoxicity from wild type (WT) or IL-6 transgenic (IL- 6TG) mice was evaluated using the chromium 51 (51Cr) release assay. NK-cell number, perforin, granzyme-B, CD69 and CD107a expression were evaluated by flow cytometry. Human polyclonal NK cells from healthy donors were cultured in the presence of Tocilizumab (TCZ), an IL-6 receptor blocker. Peripheral blood mononuclear cells (PBMC) were treated with IL-6. NK-cell cytotoxicity, perforin, granzyme-B and CD107a expression were evaluated as above. Results. Splenic NK-cell cytotoxicity was reduced in IL-6TG compared to WT mice. CD69 and CD107a levels showed no significant differences; perforin and granzyme-B expression was impaired in NK cells from IL-6TG mice. Exposure of peripheral blood human NK cells to IL-6 led to reduced perforin and granzyme-B expression. Culturing polyclonal NK cells in the presence of TCZ significantly increased cytotoxicity with increased perforin and granzyme-B. Last, in NK cells from s-JIA patients, reduction of IL-6 plasma levels during remission correlated with rescue of perforin and granzyme-B expression. Conclusions. In both mice and humans, IL-6 down-modulate NK-cell cytotoxic activity. This decrease was associated with reduced perforin and granzyme-B levels in the absence of altered granule exocytosis.