Regulation of neutrophil apoptosis in rheumatoid arthritis

中性粒细胞浸润炎性关节是类风湿关节炎（RA）的一个特征。积累的中性粒细胞通过炎症介质在关节炎症的破坏中发挥关键作用。中性粒细胞是寿命较短的细胞，可自发凋亡。许多因素已被证明可以调节自发性中性粒细胞凋亡。然而，中性粒细胞凋亡在RA中的调控机制尚未阐明。我们研究了滑膜细胞源性因子和各种抗风湿药物对中性粒细胞凋亡的调节作用。本研究的结果如下：(1)促炎因子（IL-1、TNF-α）产生可抑制中性粒细胞自发凋亡的可溶性因子。(2) GM-CSF是该活性的主要因子。(3)发现了一种新的中性粒细胞凋亡抑制因子（MW约为25 Kd）。(4) PGE2通过与中性粒细胞上的受体（EP4和EP2）结合来阻止中性粒细胞凋亡。另一方面，EP3激动剂可迅速促进中性粒细胞的独特死亡，类似于细胞凋亡。(5)在抗风湿药物中，磺胺氮嗪能快速促进中性粒细胞凋亡，亲脂性金复合物（金嘌呤）也能调节细胞死亡。这些发现表明，关节炎症可能通过抑制细胞凋亡来延长中性粒细胞的存活时间，而用于治疗RA的药物通过诱导细胞凋亡来促进中性粒细胞死亡。

Infiltration of neutrophils into the inflamed joints is a characteristic feature of rheumatoid arthritis (RA). Accumulated neutrophils play pivotal roles on destruction of the inflamed joints through the elaboration of inflammatory mediators. Neutrophils are short-lived cells and spontaneously die by apoptosis. A number of factors have been shown to modulate spontaneous neutrophil apoptosis. However, the regulatory mechanisms of neutrophil apoptosis in RA have not been elucidated. We investigated the regulatory roles of synovial cell-derived-factors and various anti-rheumatic drugs on neutophil apoptosis. The results obtained in this study are as following. (1) Pro-inflammatory cytokines (IL-1, TNF-α) produce soluble factor (s) capable of inhibiting spontaneous neutrophil apoptosis. (2) GM-CSF is a major factor for this activity. (3) A novel inhibitory factor for neutrophil apoptosis (MW about 25 Kd) has been found. (4) PGE2 prevented neutrophil apoptosis through the binding to the receptors (EP4 and EP2) on neutrophils. On the other hand, EP3 agonist rapidly promoted unique death of neutrophils resembling to apoptosis. (5) Among the anti-rheumatic drugs examined, sulfasalazine rapidly promoted neutrophil apoptosis and lipophilic gold complex (auranofin) also modulated cellular death. These findings indicate that joint inflammation potentially elongates neutrophil survival by inhibiting apoptosis and the drugs used in the treatment of RA promote neutrophil death by inducing apoptosis.