多发性骨髓瘤患者血清叉头状转录因子与白细胞介素-6的表达水平及其意义

Expression Levels and Clinical Significance of Foxp3 and Interleukin-6 in Multiple Myeloma

目的 探讨多发性骨髓瘤（MM）患者血清中叉头状转录因子（Foxp3）与白细胞介素（IL）-6的表达水平、二者的相关性关系及其临床意义.方法 选择2011年8月至2013年2月,于汕头市中心医院血液科就诊的初发MM患者34例及进展MM患者7例为研究对象.将其分别纳入初发组（n=34）与进展组（n=7）.其中,对初发MM患者进一步按照国际分期系统（ISS）分期标准将其分为：Ⅰ期组（n=3）,Ⅱ期组（n=14）,Ⅲ期组（n=17）.MM患者经4个疗程化疗后,将可进行药效学评价的患者38例,纳入化疗后组（n=38）,按照疗效进一步将其分为完全缓解（CR）组（n=7）,部分缓解（PR）与微小缓解（MR）组（n=16）及无变化（NC）与进展（PD）组（n=15）.随机选取同期于本院体检的健康个体16例纳入对照组（n=16）.本研究遵循的程序符合汕头市中心医院人体试验委员会所制定的伦理学标准,得到该委员会批准,分组征得受试对象本人的知情同意,并与之签署临床研究知情同意书.通过汕头市中心医院检验科采集研究组与对照组血液标本.采用酶联免疫吸附法（ELISA）检测受试对象血清Foxp3与IL-6表达水平.回顾性分析受试对象的临床数据：对比初发组、化疗后组与对照组血清Foxp3与IL-6的表达水平;对比初发组不同ISS分期患者血清Foxp3与IL-6的表达水平;对比研究组MM患者经化疗后,获得不同疗效的患者血清Foxp3与IL-6的表达水平;并对比研究组接受治疗前患者血清Foxp3与IL-6的表达水平,及二者之间的相关性关系及其临床意义.结果 ①初发组、化疗后组MM患者血清Foxp3表达水平均低于对照组,差异有统计学意义（P＜0.001）;初发组与化疗后组的Foxp3表达水平比较,差异无统计学意义（P＞0.05）.初发组与化疗后组的IL-6表达水平均高于对照组,差异有统计学意义（P＜0.001）;初发组与化疗后组的IL-6表达水平比较,差异无统计学意义（P＞0.05）.②对于初发组MM患者,随ISS分期增高,患者血清Foxp3表达水平呈下降趋势,但差异无统计学意义（P＞0.05）;不同分期患者血清Foxp3表达水平两两比较,差异亦无统计学意义（P＞0.05）.而血清IL-6表达水平随ISS分期增高呈上升趋势,差异有统计学意义（P＜0.05）;Ⅱ期组与Ⅲ期组MM患者血清IL-6表达水平比较,差异亦有统计学意义（P=0.009）.③研究组MM患者经化疗后,可评价疗效的患者中CR组,PR＋ MR组及NC＋PD组的Foxp3表达水平依次降低,差异有统计学意义（P＜0.05）;组间比较CR组Foxp3表达水平显著高于PR＋ MR组与NC＋PD组,差异有统计学意义（P=0.012,0.001）;PR＋MR组与NC＋ PD组Foxp3表达水平比较,差异无统计学意义（P＞0.05）.CR组,PR＋ MR组及NC＋ PD组IL-6表达水平依次升高;NC＋ PD组IL-6表达水平显著高于CR组与PR＋ MR组,差异有统计学意义（P＜0.001）;CR组与PR＋ MR组IL-6表达水平比较,差异有统计学意义（P=0.028）.④研究组MM患者化疗前血清Foxp3与IL-6表达水平呈负相关关系（r=-0.632,P＜0.01）.结论 MM患者血清Foxp3表达水平低于健康个体,Foxp3表达水平的变化可反映患者病情ISS分期层次,可作为重要的疗效预测指标.MM患者血清IL-6表达水平对MM的早期诊断、化疗疗效及病情进展监测可能具有一定的意义.MM患者血清Foxp3与IL-6表达水平的关系可能体现了MM发病机制中肿瘤与宿主免疫的动态平衡关系.

Objective To investigate the expression levels,relevance and clinical significance of forkhead box protein （Foxp3） and interleukin （IL）-6 in multiple myeloma （MM）.Methods From August 2011 to February 2013,a total of 41 MM patients in Shantou Central Hospital were collected into this study,as study group （n=41）,including newly-diagnosis group （n=34） and disease progression group （n=7）.According to the International Staging System （ISS） criteria,the newly-diagnosis group were divided into stage Ⅰ group （n=3）,stage Ⅱ group （n=14） and stage Ⅲ group （n=17）.After 4 courses of chemotherapy,38 MM patients could evaluate the efficacy.These patients were classified into after chemotherapy group （n =38）.According to the efficacy,the after chemotherapy goup were divided into complete response （CR） group （n =7）,partial response （PR） and minimal response （MR） group （n=16）,no-change （NC） and progression disease （PD） group （n-=15）.A total of 16 healthy individuals who received medical examination in the same period were included into control group （n =16）.The study protocol was approved by the Ethical Review Board of Investigation in Human at Shantou Central Hospital.Informed consent was obtained from all participants.The blood specimens from the subjects were collected at the clinical laboratory.Expression levels of Foxp3 and IL-6 were detected by enzyme-linked immunosorbent assay （ELISA）.The cilinical data of the subjects were retrospectively analyzed：expression levels of Foxp3 and IL-6 were compared among different ISS stages,efficacy and before and after treatment.The correlation and clinical significance of Foxp3 and IL-6 expression levels in MM were analyzed.Results ① Expression levels of Foxp3 were significantly reduced in MM patients compared with in levels of Foxp3 healthy controls irrespective of treatment （P〈 0.001）,and considerably equal to those in the newly-diagnosis group and after chemotherapy group （P〉 0.05）.Expression levels of IL-6 were significantly higher in MM patients compared with those in healthy controls irrespective of treatment （P〈 0.001）,and considerably equal to those in the newly-diagnosis group and the after chemotherapy group （P〉 0.05）.② Expression levels of Foxp3 were reducing along with the increasing of the ISS stages in the newlydiagnosis group,but the difference wasn＆#39;t statistically significant （P〉0.05）.And the difference in pairwise comparison of different stages either wasn＆#39;t statistically significant （P〉0.05）.Expression levels of IL-6 were elevating along with the increasing of the ISS stages （P〈0.05）.And there was a significant difference in IL-6 level between stage Ⅱ and Ⅲ group （P=0.009）.③After chemotherapy,the expression levels of Foxp3 were reduced in order of CR group,PR＋MR group and NC＋PD group（P〈0.05）.Foxp3 levels were significantly higher in CR group than those in PR＋ MR group and NC＋ PD group （P=0.012,0.001）,and there was no significant difference those in between PR＋MR group and NC＋PD group （P〉 0.05）.Expression levels of IL-6 were elevated in order of CR group,PR＋MR group and NC＋PD group.IL-6 levels in NC＋ PD group were significantly higher than those in CR group and PR＋ MR group （P〈 0.001）,and there were significant difference in IL-6 levels between PR＋MR group and CR group （P=0.028）.④ There was a negative correlation between expression levels of Foxp3 and IL-6 in the study group before chemotherapy （R=-0.632,P〈0.01）.Conclusions Expression levels of Foxp3 were significantly reduced in MM patients.The dynamic variation of Foxp3 levels may reflect patients＆#39; condition,and could be an important predictor of the efficacy.Expression level of IL-6 might contribute to early diagnosis,monitoring the chemotherapy efficacy and disease progression of patients with MM.The correlation between Foxp3 and IL-6 levels may reflect the dynamic balance between the tumor and the host immune response in the pathogenesis of MM.