Ajuebor M N, Virág L, Flower R J, Perretti M, Szabó C
Department of Biochemical Pharmacology, The William Harvey Research Institute, Charterhouse Square, London, UK.
Immunology. 1998 Dec;95(4):625-30. doi: 10.1046/j.1365-2567.1998.00644.x.
In the present study, by comparing the responses in wild-type mice and mice lacking the inducible (or type 2) nitric oxide synthase (iNOS), we investigated the role played by iNOS in the regulation of polymorphonuclear granulocyte (PMN) accumulation and chemokine production in the mouse peritoneal cavity in response to administration of zymosan (0.2 mg). Zymosan injection induced the production of nitric oxide, and triggered a time-dependent PMN immigration into the peritoneal cavity. This response was associated with increases in the level of the chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-2, monocyte chemo-attractant protein (MCP)-1 and cytokine-induced neutrophil chemo-attractant (KC), as measured in the peritoneal cavities. Injection of zymosan also induced a time-dependent increase in the production of the anti-inflammatory cytokine interleukin-10 (IL-10) in the peritoneal cavity. When comparing the response between wild-type and iNOS knockout (KO) mice, we observed that the low-level PMN accumulation measured at 1 hr was slightly but significantly increased in the absence of functional iNOS. On the other hand, the delayed response (2-4 hr after zymosan) of PMN accumulation was suppressed in the iNOS KO mice. The early enhancement of PMN infiltration in the iNOS-deficient mice was associated with increased peritoneal levels of MIP-2, KC and IL-10 proteins. The delayed suppression of PMN infiltration was associated with reduced MIP-2 and IL-10 levels in the peritoneal cavity. The lack of iNOS did not affect the release of MIP-1alpha and MCP-1 at any of the time-points studied. The current data demonstrate that iNOS regulates the production of certain CXC (but not CC) proinflammatory chemokines, the production of IL-10 and exerts a biphasic regulatory effect on PMN accumulation in zymosan-induced acute inflammation.
在本研究中，通过比较野生型小鼠和缺乏诱导型（或2型）一氧化氮合酶（iNOS）的小鼠的反应，我们研究了iNOS在调节小鼠腹腔中多形核粒细胞（PMN）积聚和趋化因子产生以响应酵母聚糖（0.2毫克）给药中的作用。注射酵母聚糖诱导一氧化氮的产生，并引发PMN随时间依赖性地迁移到腹腔。这种反应与腹腔中趋化因子巨噬细胞炎性蛋白（MIP）-1α、MIP-2、单核细胞趋化蛋白（MCP）-1和细胞因子诱导的中性粒细胞趋化因子（KC）水平的升高有关。注射酵母聚糖还诱导腹腔中抗炎细胞因子白细胞介素-10（IL-10）的产生随时间依赖性增加。当比较野生型和iNOS基因敲除（KO）小鼠的反应时，我们观察到在缺乏功能性iNOS的情况下，1小时时测得的低水平PMN积聚略有但显著增加。另一方面，iNOS KO小鼠中PMN积聚的延迟反应（酵母聚糖注射后2-4小时）受到抑制。iNOS缺陷小鼠中PMN浸润的早期增强与腹腔中MIP-2、KC和IL-10蛋白水平的增加有关。PMN浸润的延迟抑制与腹腔中MIP-2和IL-10水平的降低有关。在研究的任何时间点，iNOS的缺乏均不影响MIP-1α和MCP-1的释放。目前的数据表明，iNOS调节某些CXC（而非CC）促炎趋化因子的产生、IL-10的产生，并对酵母聚糖诱导的急性炎症中PMN的积聚发挥双相调节作用。
