Regulatory effects of interleukin-4 and interleukin-10 on human neutrophilfunction ex vivo and on neutrophil influx in a rat model of arthritis

Objective. To assess the capacity of interleukin-4 (IL-4) and IL-10 to bloc k polymorphonuclear neutrophil (PMN) activation in an ex vivo human model s ystem and to confirm their effect on neutrophil function in an animal model of arthritis. Methods. The ex vivo phagocytic capacity of cytokine-activated human PMNs w as assessed by use of assays for measuring the ingestion of heat-killed yea st and by subsequent hexose-monophosphate shunt activation using nitroblue tetrazolium reduction, The in vivo activity of IL-4 and IL-10 was measured using a rat adjuvant arthritis model in which the mycobacterial antigen con centration was titrated to modify disease intensity. Results. IL-4 and IL-10 suppressed the ex vivo activation state of interfer on-gamma- and tumor necrosis factor alpha -activated human neutrophils, In the rat adjuvant arthritis model, treatment with systemic murine IL-10 (mIL -10) effectively suppressed all disease parameters in rats that received th e lower concentrations of mycobacteria, whereas systemic mIL-4 was effectiv e against even the most severe disease., Both cytokines were effective in l owering the absolute PMN cell number recovered and the PMN activation state in the joint synovia. We also observed lower levels of the messenger RNA t ranscript for CINC protein (cytokine-induced neutrophil chemoattractant; a rat homolog for human IL-8) in the synovia. Conclusion. IL-10 is an effective antiarthritic agent and has a major effec t on the presence and function of PMNs in the joint synovia when disease in tensity is not severe. IL-4 has an inhibitory profile that is similar to th at of IL-10, but is effective in modifying even the most severe disease. Bo th cytokines reduced the phagocytic activation of human PMNs in response to proinflammatory cytokines, These data demonstrate that IL-4 and IL-10 can exert powerful regulatory effects on neutrophil function that translate int o a therapeutic response ina disease model of arthritis. Treatment with the se cytokines alone or in combination may therefore be very useful in the ma nagement of patients with rheumatoid arthritis.