Injury induces deficient interleukin-12 production, but interleukin-12 therapy after injury restores resistance to infection
Injury induces deficient interleukin-12 production, but interleukin-12 therapy after injury restores resistance to infection
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DOI：
10.1097/00000658-200002000-00015
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发表时间：
2000-02-01
影响因子：
9
通讯作者：
Rodrick, ML
中科院分区：
文献类型：
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作者：
Göebel, A;Kavanagh, E;Rodrick, ML
目的以连续的时间间隔评估损伤患者和对照受试者外周血单核细胞/巨噬细胞产生白细胞介素-12（IL-12）的情况，并使用小鼠模型来证实人类发现，并探索低剂量IL-12治疗在恢复损伤后对感染的抵抗力方面的有效性。但对受伤患者中IL-12的产生知之甚少。作者先前报道，在烧伤小鼠模型中，早期、中等剂量的IL-12治疗恢复了对后期感染性攻击（盲肠结扎和穿刺，CLP）的抵抗力。然而，临床相关的低剂量IL-12治疗进行或超过脓毒症的时间challenge. MethodsPeripheral blood mononuclear cells（PBMC）和贴壁细胞的疗效仍有待测试，从27例严重烧伤或创伤性损伤和18名健康人，并进行了研究，在一系列的时间间隔刺激细菌脂多糖（LPS）的IL-12生产。还研究了来自18名相同患者的PBMC的IL-10产生。从烧伤或假烧伤小鼠脾贴壁细胞IL-12的生产进行了研究，在一系列的时间间隔后受伤，以确认人类的发现。每隔一天向烧伤和假烧伤小鼠组给予低剂量IL-12或载体，然后在第10天用CLP攻击，并确定存活率。最后，从CLP后接受低剂量IL-12或媒介物的烧伤或假烧伤动物收获脾脏。后脾细胞的血细胞计数器测定，脾细胞培养和生产的肿瘤坏死因子-α，干扰素-γ，和IL-10进行了评估，通过免疫测定。ResultsAdhesive cells从患者的PBMC产生的IL-12比正常的PBMC损伤后，达到最低点8至14天后损伤。LPS刺激PBMCs后8~14d，PBMCs产生IL-12的能力显著低于健康人，而产生IL-10的能力显著高于健康人。低剂量IL-12治疗显著增加CLP后的生存率。与溶剂处理的烧伤动物相比，IL-12处理的烧伤小鼠的脾细胞在CLP前后TNF-α和IF-γ的产生均显著增加。IL-12处理后，烧伤脾细胞产生的IL-10仍然很高。脾细胞增加后IL-12治疗烧伤mice. ConclusionThe能力产生IL-12的单核细胞/巨噬细胞系的粘附细胞在人类和小鼠烧伤模型严重损伤后显着降低。在人类中，在损伤后约1周，IL-12产生减少和IL-10产生增加之间存在相互关系。小鼠烧伤模型中的低剂量IL-12治疗显着提高了脓毒症激发后的生存率，即使治疗持续到脓毒症发作之后。低剂量IL-12治疗小鼠增加了在宿主防御中重要的促炎介质的产生，同时维持或增加了IL-10（一种重要的促炎细胞因子）的产生。
ObjectiveTo assess at serial intervals the production of interleukin-12 (IL-12) by monocytes/macrophages from the peripheral blood of injured patients and control subjects, and using a mouse model to confirm human findings and explore the effectiveness of low-dose IL-12 therapy in restoring resistance to infection after injury.Summary Background DataSerious injury is associated with loss of function of the T helper 1 lymphocyte phenotype, but little is known about IL-12 production in injured patients. The authors previously reported that early, moderate-dose IL-12 therapy in a mouse model of burn injury restored resistance to a later infectious challenge (cecal ligation and puncture, CLP). However, the efficacy of clinically relevant low-dose IL-12 therapy carried out to or beyond the time of septic challenge remains to be tested.MethodsPeripheral blood mononuclear cells (PBMCs) and adherent cells were obtained from 27 patients with major burns or traumatic injury and 18 healthy persons and were studied at serial intervals for IL-12 production stimulated by bacterial lipopolysaccharide (LPS). PBMCs from 18 of the same patients were studied for IL-10 production as well. IL-12 production by adherent cells from the spleens of burn or sham burn mice was studied at serial intervals after injury to confirm the human findings. Low-dose IL-12 or vehicle was given every other day to groups of burn and sham burn mice, which were then challenged with CLP on day 10, and survival was determined. Finally, spleens were harvested from burn or sham burn animals receiving low-dose IL-12 or vehicle after CLP. After splenic cellularity was determined by hemocytometer, splenocytes were cultured and production of tumor necrosis factor-alpha, interferon-gamma, and IL-10 were assessed by immunoassay.ResultsAdherent cells from patients' PBMCs produced significantly less IL-12 than normal PBMCs after injury, reaching a nadir 8 to 14 days after injury. Stimulation of whole PBMCs by LPS indicated that at 8 to 14 days after injury, IL-12 production by PBMCs was significantly lower and IL-10 production was significantly higher than that of PBMCs from healthy persons. Low-dose IL-12 therapy significantly increased survival after CLP. Splenocytes from burn mice treated with IL-12 had significantly increased production of TNF-alpha and IF-gamma, both before and after CLP, when compared with vehicle-treated burn animals. IL-10 production by burn splenocytes remained high after IL-12 treatment. Splenic cellularity increased after IL-12 treatment in burn mice.ConclusionThe capacity to produce IL-12 by adherent cells of the monocyle/macrophage lineage is significantly reduced after serious injury in humans and in a mouse burn model. In humans, there is a reciprocal relation between diminished IL-12 production and increased IL-10 production at approximately 1 week after injury. Low-dose IL-12 therapy in the mouse burn model markedly increased survival after a septic challenge, even when treatment was carried beyond the onset of sepsis. Low-dose IL-12 treatment in the mouse increased production of proinflammatory mediators important in host defense and at the same time maintained or increased production of IL-10, an important antiinflammatory cytokine.