[核因子-κB在癌症恶病质中的作用]

[Role of NF-kappa B in cancer cachexia].

作者信息

Zhou Wei, Jiang Zhi-Wei, Jiang Jun, Li Ning, Li Jie-Shou

机构信息

Research Institute of General Surgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, China.

出版信息

Zhonghua Wai Ke Za Zhi. 2004 Jun 7;42(11):683-6.

PMID:15329260

Abstract

OBJECTIVE

To assess the putative involvement of NF-kappaB and pro-inflammatory cytokines in the pathogenesis of cancer cachexia and the therapeutic efficacy of indomethacin (IND) on cachexia.

METHODS

Thirty young male BALB/c mice were divided randomly into five groups: A, control; B, tumor-bearing plus saline; C, tumor-bearing plus IND (0.25 mg/kg); D, tumor-bearing plus IND (0.5 mg/kg); and E, tumor-bearing plus IND (2.0 mg/kg). Colon 26 adenocarcinoma cells of murine were inoculated subcutaneously to induce cachexia. Saline and IND were given intraperitoneally daily for 7 days from the onset of cachexia to sacrifice. Food intake and body composition were documented, serum TNF-alpha and IL-6 levels and activity of NF-kappaB in spleen were investigated in all animals.

RESULTS

Cachexia was observed in all tumor-bearing mice. No difference was found between groups in food intake (P > 0.05). By day 16, body weights of non-tumor mice were about 82.0% of healthy controls (P < 0.01), and the weight of gastrocnemius was decreased by 28.7% (P < 0.01). Gastrocnemius weight was increased markedly (P < 0.01) after treatment of IND (0.5 mg/kg). Tumor-bearing caused a significant increase in serum TNF-alpha and IL-6 levels (P < 0.01). The concentration of TNF-alpha (P < 0.05) and IL-6 (P < 0.01) in tumor-bearing mice was reduced after administration of 0.5 mg/kg IND for 7 days. NF-kappaB activation in the spleen was increased in tumor-bearing mice in comparison with controls. NF-kappaB activity was reduced in mice treated with IND. The maximal inhibition was observed at an dosage of 0.5 mg/kg (P < 0.01). Liner positive correlation was found between NF-kappaB activity and cytokine levels (r(TNF-alpha) = 0.918, P(TNF-alpha) = 0.028; r(IL-6) = 0.884, P(IL-6) = 0.046).

CONCLUSIONS

Cachexia induced by colon 26 adenocarcinoma cells may be partially attributed to the enhanced TNF-alpha and IL-6 levels which is controlled by NF-kappaB. IND may inhibit the activation of NF-kappaB, decrease serum TNF-alpha and IL-6 levels and thus alleviate the cachexia.

摘要

目的

评估核因子-κB（NF-κB）和促炎细胞因子在癌症恶病质发病机制中的假定作用以及吲哚美辛（IND）对恶病质的治疗效果。

方法

将30只年轻雄性BALB/c小鼠随机分为五组：A组为对照组；B组为荷瘤加生理盐水组；C组为荷瘤加IND（0.25mg/kg）组；D组为荷瘤加IND（0.5mg/kg）组；E组为荷瘤加IND（2.0mg/kg）组。皮下接种鼠结肠26腺癌细胞以诱导恶病质。从恶病质开始至处死，每天腹腔注射生理盐水和IND，持续7天。记录所有动物的食物摄入量和身体组成，检测血清肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）水平以及脾脏中NF-κB的活性。

结果

所有荷瘤小鼠均出现恶病质。各组间食物摄入量无差异（P>0.05）。到第16天，非荷瘤小鼠体重约为健康对照组的82.0%（P<0.01），腓肠肌重量下降28.7%（P<0.01）。IND（0.5mg/kg）治疗后腓肠肌重量显著增加（P<0.01）。荷瘤导致血清TNF-α和IL-6水平显著升高（P<0.01）。给予0.5mg/kg IND 7天后，荷瘤小鼠中TNF-α（P<0.05）和IL-6（P<0.01）的浓度降低。与对照组相比，荷瘤小鼠脾脏中NF-κB的激活增加。IND治疗的小鼠中NF-κB活性降低。在剂量为0.5mg/kg时观察到最大抑制作用（P<0.01）。发现NF-κB活性与细胞因子水平呈线性正相关（r（TNF-α）=0.918，P（TNF-α）=0.028；r（IL-6）=0.884，P（IL-6）=0.046）。