Inhibition of Natural Killer Cell Cytotoxicity by Interleukin‐6: Implications for the Pathogenesis of Macrophage Activation Syndrome

Abstract

Objective Systemic juvenile idiopathic arthritis (JIA) is associated with high levels of interleukin‐6 (IL‐6) in the serum and synovial fluid, and impairment of natural killer (NK) cell function is often observed. This study was undertaken to evaluate a possible link between these 2 biologic findings and whether they may be associated with the development of macrophage activation syndrome, a condition frequently observed in systemic JIA. Methods Splenocytes from wild‐type (WT) or IL‐6–transgenic (Tg) mice were evaluated for NK cell cytotoxicity using a 51Cr‐release assay. Numbers of NK cells and expression of perforin, granzyme B, CD69, and CD107a were evaluated by flow cytometry. Human peripheral blood mononuclear cells (PBMCs) isolated from healthy donors were treated with IL‐6 and cultured in the presence or absence of tocilizumab (TCZ), an IL‐6 receptor blocker. Human polyclonal NK cells from healthy donor PBMCs were evaluated for cell cytotoxicity and expression of perforin, granzyme B, and CD107a. PBMCs harvested from patients with systemic JIA during periods of active or inactive disease were left untreated or treated with IL‐6 in combination with soluble IL‐6 receptor and analyzed for the expression of perforin and granzyme B. Results Splenic NK cell cytotoxicity was reduced in IL‐6–Tg mice compared to WT mice. Levels of CD69 and CD107a showed no significant differences, whereas expression of perforin and granzyme B was impaired in NK cells from IL‐6–Tg mice. Exposure of human peripheral blood NK cells to IL‐6 led to reduced expression of perforin and granzyme B. Culturing human polyclonal NK cells in the presence of TCZ significantly increased cell cytotoxicity, and also increased expression of perforin and granzyme B. In patients with systemic JIA, a reduction in IL‐6 plasma levels during disease remission correlated with the rescue of perforin and granzyme B expression in NK cells from these patients. Conclusion In both mice and humans, IL‐6 down‐modulated the cytotoxic activity of NK cells. This decrease was associated with reduced perforin and granzyme B levels in the absence of altered granule exocytosis.

A cytokine signal inhibitor for rheumatoid arthritis enhances cancer metastasis via depletion of NK cells in an experimental lung metastasis mouse model of colon cancer

“…In that study, no significant differences in NK cell expression of CD69 or CD107a were observed between IL-6 transgenic, and wild-type mice. However, perforin and granzyme expression in NK cells was reduced in IL-6 transgenic mice compared with that in wild-type mice (36). Therefore, it may be assumed that NK cell activity is inhibited by IL-6; however, in the present study, the IL-6R Ab did not affect NK cell numbers or maturation, and did not promote cancer metastasis in the lung metastasis mouse model.…”

“…These same signaling pathways serve to maintain cell progression towards neoplastic growth, protecting cells from apoptotic death (35). With regards to NK cell activity, a previous study reported that human NK cells exposed to IL-6 exhibited reduced perforin and granzyme-B expression, which was recovered in the presence of the anti-human IL-6R Ab tocilizumab (36). In that study, no significant differences in NK cell expression of CD69 or CD107a were observed between IL-6 transgenic, and wild-type mice.…”

Advances in the pathogenesis of primary and secondary haemophagocytic lymphohistiocytosis: differences and similarities

“…Perforin and granzyme B expression of NK cells was reduced in IL6-overexpressing mice, resulting in defective cytotoxicity. Treatment of human NK cells with tocilizumab, an anti-IL6 antibody, increased perforin and granzyme B expression, enhancing their cytotoxic capacity (Cifaldi et al, 2015).…”

“…Constitutively high IL6 expression excessively amplified the inflammatory response to Poly(I:C), CpG, lipoteichoic acid and lipopolysaccharide, the latter inducing fulminant HLH. Thus, prolonged exposure to IL6, as observed in different autoimmune and autoinflammatory diseases, not only impairs NK cell cytotoxicity but also derails the immune system towards hyperinflammatory responses (Strippoli et al, 2012;Cifaldi et al, 2015).…”

Dendritic Cell–Derived IL-32α: A Novel Inhibitory Cytokine of NK Cell Function

“…Thus, IL-32a is added to the list of other cytokines that inhibit NK cell functions. For example, IL-6 has been shown to antagonize NK cytotoxicity by reducing granzyme B and perforin in the systemic juvenile idiopathic arthritis murine model, and its presence in patient sera was correlated with lower NK activity (58). TGF-b is known to reduce NK cell function by repressing the mTor pathway (59) and downregulating NKG2D or DAP10 expression, leading to an impaired cytotoxic activity of human NK cells (44,60).…”