Variation and significance of IL-2R, IL-6, IL-8 and TNF-α in diffuse large B-cell lymphoma
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摘要: 目的 探究细胞因子IL-2R、IL-6、IL-8、TNF-α在弥漫性大B细胞淋巴瘤(DLBCL)中的变化及其意义。方法 收集上海交通大学医学院附属瑞金医院收治的155例R-CHOP(利妥昔单抗、环磷酰胺、阿霉素、长春新碱和泼尼松)方案治疗后达完全缓解且无进展生存期≥24个月的DLBCL患者(持续缓解组)和45例R-CHOP方案治疗后达完全缓解但是在2年内复发的DLBCL患者(复发组)。持续缓解组患者于治疗前、第6个周期治疗开始前以及持续缓解治疗结束1年后采血，复发组患者于治疗前、第6个周期治疗开始前及复发时间点采血。采用IMMUNITE 1000化学发光分析仪检测细胞因子IL-2R、IL-6、IL-8、TNF-α的含量。结果 IL-2R、IL-6及TNF-α含量在Ⅲ~Ⅳ期、ECOG评分≥2分、结外受累个数≥2个、IPI评分≥3分的DLBCL患者中显著升高(P＜0.05)；IL-8在IPI评分≥3分和双表达淋巴瘤(DEL)的患者中显著升高(P＜0.05)；IL-6在non-GCB亚型中显著升高(P＜0.05)。复发组患者治疗前血清细胞因子IL-2R、IL-6、TNF-α含量均较持续缓解组显著升高(P＜0.05)。治疗6个周期开始前同治疗前比较，复发组和持续缓解组IL-2R、IL-6、IL-8、TNF-α含量均显著降低(P＜0.05)，以上指标在持续缓解组持续降低，而复发组在复发时又显著升高(P＜0.05)。IL-2R含量≥1398 U/mL(P＜0.001)、IL-6含量≥7.1 pg/mL(P=0.004)、TNF-α含量≥19.5 pg/mL(P＜0.001)与短的总生存期显著相关。结论 治疗前复发组和持续缓解组患者IL-2R、IL-6、IL-8、TNF-α含量存在明显差异，且以上指标在缓解时降低，复发时再次升高，或许可成为预测和评估DLBCL患者R-CHOP治疗后复发的有效血清标记分子。此外，治疗前血清中高的IL-2R、IL-6及TNF-α与DLBCL患者不良预后相关。Abstract: Objective To investigate the variation and significance of IL-2R, IL-6, IL-8 and TNF-α levels in diffuse large B-cell lymphoma(DLBCL).Methods A total of 155 cases of DLBCL with complete remission and progression free survival ≥ 24 months after R-CHOP treatment(continuous remission group) and 45 cases of relapsed DLBCL within 2 years after R-CHOP treatment(relapse group) were collected from Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine. Blood samples were collected from patients of the continuous remission group at 3 time points, before treatment, before the start of the 6th cycle of treatment and one year after the end of continuous remission. Patients in the relapse group were sampled before treatment, before the start of the 6th cycle of treatment and at the time of relapse. The contents of inflammatory cytokines IL-2R, IL-6, IL-8 and TNF-α were detected by IMMUNITE 1000 chemiluminescence analyzer.Results The levels of IL-2R, IL-6 and TNF-α were significantly increased in DLBCL patients with Ann Arbor stage of Ⅲ-Ⅳ, ECOG score≥2, number of extranodal involvement≥2, IPI score≥3 (P < 0.05), while IL-8 level was significantly increased in patients with IPI score≥3 and DEL(P < 0.05) and IL-6 was significantly increased in non-GCB subtype(P < 0.05). The levels of serum cytokines IL-2R, IL-6 and TNF-α in the relapse group were significantly higher than those of the continuous remission group before treatment(P < 0.05). Compared with those before treatment, IL-2R, IL-6, IL-8 and TNF-α levels in the relapse group and the continuous remission group were significantly decreased before the start of the 6th cycle of treatment(P < 0.05), and the levels of the above cytokines continued to decreased in the continuous remission group while increased in the relapse group(P < 0.05). IL-2R content≥1398 U/mL(P < 0.001), IL-6 content ≥7.1 pg/mL(P=0.004), TNF-α content ≥19.5 pg/mL(P < 0.001) were significantly associated with shorter overall survival.Conclusion The levels of IL-2R, IL-6, IL-8 and TNF-α were significantly different between the relapsed group and the continuous remission group before treatment, and these cytokines levels were obviously decreased following remission while increased again when recurrence, which may be effective serum markers for predicting and evaluating the recurrence of DLBCL patients after R-CHOP treatment. In addition, high levels of serum IL-2R, IL-6, and TNF-α before initiation of treatment were associated with poor prognosis in DLBCL patients.
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Key words:
- diffuse large-B cell lymphoma /
- continuous remission /
- relapse /
- IL-2R /
- IL-6 /
- IL-8 /
- TNF-α
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表 1 不同临床病理特征DLBCL患者的血清细胞因子含量比较
M(P25，P75) 临床特征 IL-2R/(U·mL-1) IL-6/(pg·mL-1) IL-8 /(pg·mL-1) TNF-α/(pg·mL-1) Ann Arbor分期 Ⅰ~Ⅱ(n=121) 484.0(369.0，748.0) 3.1(2.0，6.1) 51.6(26.1，142.0) 8.8(6.6，10.9) Ⅲ~Ⅳ(n=79) 1 614.0(847.0，4 659.0) 7.1(3.3，18.0) 71.0(33.5，219.5) 17.0(11.0，30.6) P ＜0.001 ＜0.001 0.174 ＜0.001 ECOG评分 0~1(n=184) 642.5(418.5，1 367.3) 3.8(2.0，8.2) 58.6(26.1，172.0) 10.3(7.5，15.7) ≥2(n=16) 1 835.0(899.8，7 500.0) 14.8(2.9，35.6) 71.8(44.6，163.0) 16.5(12.2，26.3) P 0.001 0.011 0.494 0.015 结外受累个数 0~1(n=147) 565.0(395.5，1 136.0) 3.7(2.0，7.5) 51.8(25.8，160.0) 9.7(6.9，14.6) ≥2(n=53) 1 311.0(687.0，3 954.0) 5.0(2.4，18.2) 76.9(39.3，175.0) 14.6(10.2，26.0) P ＜0.001 0.023 0.207 ＜0.001 IPI评分 0~2(n=148) 511.0(394.5，1 058.8) 3.2(2.0，6.8) 49.3(24.9，142.6) 9.4(6.8，13.8) ≥3(n=52) 1 653.0(956.5，5 307.8) 9.9(3.8，19.8) 93.8(52.0，270.3) 17.4(11.2，30.6) P ＜0.001 ＜0.001 0.001 ＜0.001 DELa) 是(n=41) 674.0(358.0，2 015.0) 3.9(2.0，11.7) 40.5(20.8，94.0) 10.3(7.0，19.5) 否(n=158) 686.5(434.0，1 387.8) 3.8(2.0，9.2) 68.2(31.5，179.5) 9.4(6.8，13.8) P 0.873 0.695 0.047 0.131 Hans分型 GCB(n=87) 622.0(440.0，1 188.0) 3.4(2.0，6.0) 55.1(26.1，171.0) 10.1(6.9，14.6) non-GCB(n=113) 805.0(409.0，1 946.0) 4.8(2.2，12.8) 62.4(28.0，195.0) 10.5(8.1，19.7) P 0.180 0.013 0.433 0.189 注：a)1例患者是否为DEL未知。 
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表 2 2组患者治疗前血清细胞因子含量比较
M(P25，P75) 组别 IL-2R/(U·mL-1) IL-6/(pg·mL-1) IL-8/(pg·mL-1) TNF-α/(pg·mL-1) 复发组(n=45) 1 571.0(693.0，4 082.0) 7.1(2.6，17.6) 71.0(25.7，177.0) 14.7(10.2，29.4) 持续缓解组(n=155) 581.0(403.0，1 188.0) 3.5(2.0，7.8) 59.4(27.7，171.0) 9.9(7.0，15.0) P ＜0.001 0.010 0.630 ＜0.001
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表 3 持续缓解组患者初发、缓解、持续缓解时血清细胞因子含量的比较
M(P25，P75) 细胞因子 治疗前 治疗6个周期开始前 持续缓解 IL-2R/(U·mL-1) 581.0(403.0，1 188.0) 452.0(356.0，588.0)1) 377.0(307.0，486.0)1)2) IL-6/(pg·mL-1) 3.5(2.0，7.8) 2.6(2.0，4.2)1) 2.0(2.0，2.6)1)2) IL-8/(pg·mL-1) 59.4(27.7，171.0) 20.5(9.7，47.8)1) 18.7(8.9，43.0)1) TNF-α/(pg·mL-1) 9.9(7.0，15.0) 8.1(6.5，10.4)1) 6.1(5.0，8.2)1)2) 与治疗前比较，1)P＜0.05；与治疗6个周期开始前比较，2)P＜0.05。
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表 4 复发组患者初发、缓解、复发时血清细胞因子含量的比较
M(P25，P75) 细胞因子 治疗前 治疗6个周期开始前 复发期 IL-2R/(U·mL-1) 1 571.0(693.0，4 082.0) 491.0(385.5，646.0)1) 940.0(472.5，2 112.5)2) IL-6/(pg·mL-1) 7.1(2.6，17.6) 3.4(2.0，4.8)1) 6.4(4.4，10.8)2) IL-8/(pg·mL-1) 71.0(25.7，177.0) 25.2(14.7，53.9)1) 74.4(27.6，113.2)2) TNF-α/(pg·mL-1) 14.7(10.2，29.4) 7.4(5.7，8.9)1) 9.6(6.2，18.4)1) 与治疗前比较，1)P＜0.05；与治疗6个周期开始前比较，2)P＜0.05。
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