Regulation of neutrophil apoptosis in rheumatoid arthritis

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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.