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Effects of IL-6 and IL-6 blockade on neutrophil function in vitro and in vivo

机译：IL-6和IL-6阻断剂对中性粒细胞功能的影响

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Objectives: Reports on the regulation of neutrophil function by IL-6 are often conflicting. Therapeutic inhibition of IL-6 in RA is associated with occasional neutropenia, but the mechanisms underlying this observation are poorly understood. This study investigated interactions between IL-6, the anti-IL-6 receptor agent tocilizumab (TCZ) and neutrophils in vitro and in vivo. Methods: Neutrophils were isolated from healthy controls and incubated in vitro with pharmacologically relevant concentrations of IL-6 or TCZ. Neutrophils were also isolated from RA patients, including a cohort following TCZ therapy. Apoptosis was measured by annexin V/propidium iodide (PI) flow cytometry; phagocytosis was measured by incubating apoptotic neutrophils with THP-1-derived macrophages; chemotaxis was measured using cell migration through hanging-cell inserts towards IL-8 and cell surface proteins, including adhesion molecules CD11b (αMβ2 integrin) and CD62L (L-selectin) were measured by flow cytometry. Results: IL-6 (10-100 ng/ml) did not affect the rate of neutrophil apoptosis, priming of the respiratory burst or adhesion molecule expression nor act as a neutrophil chemoattractant. However, IL-6 enhanced signal transducer and activator of transcription 3 (STAT3) activation and neutrophil migration towards IL-8. TCZ in vitro did not induce apoptosis or phagocytosis of neutrophils, nor did it have a significant effect upon apoptosis or cell surface molecule expression. Neutrophil functions in ex vivo neutrophils from RA patients receiving TCZ treatment were unaffected. Conclusion: Therapeutic blockade of IL-6, while inducing a transient neutropenia, does not directly affect neutrophil functions associated with host defence. TCZ-associated neutropenia cannot be explained by direct induction of apoptosis by TCZ, induction of apoptosis following depletion of IL-6, nor increased phagocytosis of neutrophils.
机译：目的：关于IL-6对嗜中性粒细胞功能的调节的报道常常是矛盾的。 RA中IL-6的治疗抑制作用与偶发性中性粒细胞减少有关，但对该机制的了解甚少。这项研究调查了IL-6，抗IL-6受体药物tocilizumab（TCZ）与嗜中性粒细胞在体外和体内的相互作用。方法：从健康对照组中分离中性粒细胞，并与药理学相关浓度的IL-6或TCZ在体外孵育。还从RA患者（包括TCZ治疗后的队列患者）中分离出中性粒细胞。通过膜联蛋白V /碘化丙啶（PI）流式细胞仪检测细胞凋亡。通过将凋亡的中性粒细胞与THP-1衍生的巨噬细胞孵育来测定吞噬作用。使用细胞通过悬液插入细胞向IL-8迁移来测量趋化性，并通过流式细胞仪测量细胞表面蛋白，包括粘附分子CD11b（αMβ2整联蛋白）和CD62L（L-选择蛋白）。结果：IL-6（10-100 ng / ml）不会影响中性粒细胞凋亡的速度，呼吸爆发的启动或粘附分子的表达，也不会充当中性粒细胞的化学吸引剂。但是，IL-6增强了信号转导子和转录激活子3（STAT3）的激活以及嗜中性粒细胞向IL-8的迁移。体外TCZ不会诱导中性粒细胞凋亡或吞噬作用，也对凋亡或细胞表面分子表达没有显着影响。接受TCZ治疗的RA患者离体中性粒细胞的中性粒细胞功能不受影响。结论：IL-6的治疗性阻断在诱导短暂性中性粒细胞减少的同时，并不直接影响与宿主防御相关的嗜中性白细胞功能。 TCZ相关的嗜中性白血球减少症不能通过TCZ直接诱导凋亡，IL-6耗尽后诱导细胞凋亡或嗜中性粒细胞吞噬作用增加来解释。

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