氯氮平对不同病程女性精神分裂症患者血清白细胞介素6及可溶性白细胞介素6受体的影响

目的：探讨女性精神分裂症患者血清白细胞介素6(IL-6)、可溶性白细胞介素6受体(sIL-6R)治疗前后变化及其与抗精神病药物氯氮平血清水平的关系。方法：采用酶联免疫吸附法测定40例女性精神分裂症患者(病程≥5年组和病程&;lt;5年组，每组20例)治疗前及治疗后第1、2和4周血清IL-6和sIL-6R水平，同时用高效液相色谱法测定氯氮平水平，以20例女性健康者血清IL-6、sIL-6R水平作对照。治疗前与治疗后第4周评定阴性和阳性症状量表(PANSS)各一次。结果：①病程≤5年组患者治疗前血清IL-6和sIL-6R水平均显著高于正常对照组(P&;lt;0．01)；治疗后第1、2和4周血清IL-6和sIL-6R水平均显著低于对照组(P&;lt;0．01)。②病程&;gt;5年组患者治疗前及治疗后第1，2和4周血清IL-6、sIL-6R水平均显著低于正常对照组(P&;lt;0．01)。③除病程&;gt;5年组患者第1周血清IL-6水平与氯氮平水平呈负相关(r=0．57，P&;lt;0．01)外，余各时点血清sIL-6R水平与氯氮平水平均无显著相关性(r=-0．36～0．17，P&;gt;0．05)。④氯氮治疗4周后，PANSS减分率与IL-6，sIL-6R减分率无显著相关(r=-0．22～-0．01．P&;gt;0．05)。结论：女性精神分裂症患者血清IL-6、sIL-6R水平与健康女性差异显著，氯氮平对IL-6和sIL-6R有抑制作用，氯氮平的抗精神病作用可能与对IL-6，sIL-6R的调节作用有关。     

女性首发精神分裂症患者血清白细胞介素6水平与氯氮平用量及症状改善的关系

背景:白细胞介素6是机体在免疫活动过程中产生的一种细胞因子。首发女性精神分裂症患者在服用氯氮平治疗后血清中白细胞介素6的变化是否为药物直接作用的结果及其是否与精神病症状的变化直接相关等问题尚需探讨。目的:观察女性首发精神分裂症患者血清白细胞介素6水平变化及其与氯氮平用量和症状改善的关系。设计:非随机同期病例-对照观察。单位:新乡医学院第二附属医院精神科。对象:于2005-05/12选取河南省精神病医院收治的精神分裂症女性患者20例为精神分裂症组。均符合中国精神障碍分类与诊断标准第3版精神分裂症的诊断标准;阳性症状与阴性症状量表评分>60分;未经治疗或门诊治疗至少2周未用药。排除有躯体疾病、内分泌及免疫系统疾病、营养不良及其他精神疾患,有过敏及激素治疗史,接受过免疫制剂治疗,近期内进行预防接种,怀孕或哺乳期妇女。对照组:同期选取年龄、性别与精神分裂症组差异无显著性意义的健康女性志愿者20例,排除标准同精神分裂症组。入组时均经受试者或监护人知情同意。方法:精神分裂症组患者均单一使用氯氮平,以25～50mg/d开始逐渐加量,3周内加到最大剂量,以最大疗效和最小副作用为用药原则。①采用酶联免疫吸附法测定精神分裂症组患者治疗前及治疗后第1,2,4周血清白细胞介素6水平。②采用高效液相色谱法测定氯氮平含量,以对照组受试者血清白细胞介素6水平作对照。③精神症状变化与白细胞介素6变化的相关分析:将患者治疗前、治疗后1,2,4周血清白细胞介素6水平分别与对应时段的阳性症状与阴性症状量表阳性症状分、阴性症状分、一般病理分、总分进行相关分析。主要观察指标:①氯氮平治疗前及治疗后各时间点患者血清白细胞介素6水平。②血清白细胞介素6水平与氯氮平含量的相关分析。③精神症状变化和血清白细胞介素6水平变化的相关分析。结果:①氯氮平治疗前及治疗后各时间点患者血清白细胞介素6水平:精神分裂症组患者治疗前血清白细胞介素6水平显著高于对照组[分别为(137.72±18.84),(65.05±20.95)ng/L,t=11.53,P<0.01],治疗后第1,2,4周均显著低于对照组[分别为(28.11±5.42),(8.48±1.14),(13.90±2.55),(65.05±20.95)ng/L,t=7.63,12.01,10.84,P<0.01]。②血清白细胞介素6水平与氯氮平含量的相关分析:治疗后第1,2,4周血清白细胞介素6水平与氯氮平含量均无显著相关性(r=-0.15,0.12,-0.29,P>0.05)。③精神症状变化和血清白细胞介素6水平变化的关系:精神分裂症组患者治疗前白细胞介素6水平与阳性症状分呈显著正相关(r=0.386,P<0.01),治疗后1,2,4周血清白细胞介素6水平与阳性症状与阴性症状量表总分及各因子分相关分析结果显示无显著相关性(r=0.136～0.237,P>0.05)。结论:女性首发精神分裂症患者血清白细胞介素6水平高于健康女性,氯氮平治疗可降低患者血清白细胞介素6水平,精神分裂症状改善与白细胞介素6变化无显著相关性。     

慢性肾功能不全患者血清白细胞介素6和可溶性白细胞介素6受体检测及临床意义

目的：探讨慢性肾功能不全患者血清白细胞介素6（IL-6）和可溶性白细胞介素6受体肝（sIL-6R）检测的临床意义。方法：采用ELISA法检测慢性肾功能不全各期及血液透析患者血清IL-6和sIL-6R变化及两者相关性。结果：肾功能不全代偿期IL-6和sIL-6R水平与正常对照组比较无明显改变（P＞0.05），氮质血症期开始逐渐上升（P＜0.05），尿毒症期和血液透析患者IL-6和sIL-6R水平与正常对照比较，其差异有极显著意义（P＜001），且两者之间有良好相关性（r=0.56，P＜0.01），患者血清IL－6和sIL-6R与血清尿素氮相关明显（r=0．49，P＜0.05）。28例血液透析患者透析后IL－6水平较透析前无明显改变（P＞0.05），但sIL－6R水平透析后显著降低（P＜0.05）。结论：IL－6和sIL－6R水平可作为判断病情和预后的指标。     

氯氮平对精神分裂症患者血浆及脑脊液中白细胞介素6的影响

目的：研究氯氮平治疗精神分裂症患者前后血浆及脑脊液中白细胞介素6(IL-6)的变化，以及精神分裂症患者的免疫状态和抗精神病药物对免疫学指标的影响。方法：实验组为新乡医学院第二附属医院住院的符合中国精神疾病诊断标准及分类方案第三版精神分裂症偏执型诊断标准的首发精神分裂症患者(n=30)，入组后单独应用氯氮平治疗[氯氮平最大剂量150～400mg／d，平均剂量(290&;#177;70)mg／d]；对照组为患者家属及非精神疾患的轻微脑损伤并脑脊液检查正常患者(n=20)。采用酶联免疫吸附法测定对照组和实验组血浆及脑脊液中IL-6的水平，并进行组间比较。结果：实验组在治疗前血浆及脑脊液IL-6水平分别为(46．73&;#177;23．27)和(10．41&;#177;8．40)ng／L，比对照组显著增高，差异有显著性意义(t=2．23，P&;lt;0．05)；实验组治疗6周症状缓解后，血浆IL-6水平[(49．34&;#177;25．24)ng／L]较对照组显著增高，差异有显著性意义(P&;lt;0．05)。结论：精神分裂症患者存在免疫功能紊乱，氯氮平治疗可改善其免疫功能。     

精神分裂症患者康复过程中血浆白细胞介素-6及其受体的变化

目的 探讨精神分裂症患者在康复过程中自细胞介素-6(IL-6)及其可溶性受体(sIL-6R)的动态变化。方法 使用ELSIA方法检测45例首发精神分裂症甚者治疗前后IL-6、sIL-6R的含量。结果 研究组IL-6水平[(21．2&;#177;2．0)ng／L]较对照组[(18．1&;#177;3．4)ng／L]增高(t=2．419，P&;lt;0．05)；sIL-6R水平[(32．0&;#177;14．3)ng／L]较对照组[(24．3&;#177;14．9)ng／L]增高(t=2．435．P&;lt;0．05)；氯氮平治疗后血浆IL-6水平为(23．5&;#177;2．4)ng／L较治疗前增高，(t=2．251，P&;lt;0．05)，IL-6升高幅度与氯氮平药物剂量呈正相关(R^2=0．533，P=0．000)；治疗后sIL-6R含量为(22．4&;#177;17．5)ng／L，较治疗前含量明显降低(t=2．174，P&;lt;0．05)。结论 精神分裂症患者IL-6及其受体含量增高，精神分裂症患者存在细胞因子的失衡；在康复过程中IL-6及sIL-6R存在不同的变化趋势。     

氯氮平对精神分裂症患者血浆及脑脊液中白细胞介素6的影响

目的:研究氯氮平治疗精神分裂症患者前后血浆及脑脊液中白细胞介素6(IL-6)的变化,以及精神分裂症患者的免疫状态和抗精神病药物对免疫学指标的影响。方法:实验组为新乡医学院第二附属医院住院的符合中国精神疾病诊断标准及分类方案第三版精神分裂症偏执型诊断标准的首发精神分裂症患者(n=30),入组后单独应用氯氮平治疗犤氯氮平最大剂量150～400mg/d,平均剂量(290±70)mg/d犦;对照组为患者家属及非精神疾患的轻微脑损伤并脑脊液检查正常患者(n=20)。采用酶联免疫吸附法测定对照组和实验组血浆及脑脊液中IL-6的水平,并进行组间比较。结果:实验组在治疗前血浆及脑脊液IL-6水平分别为(46.73±23.27)和(10.41±8.40)ng/L,比对照组显著增高,差异有显著性意义(t=2.23,P<0.05);实验组治疗6周症状缓解后,血浆IL-6水平犤(49.34±25.24)ng/L犦较对照组显著增高,差异有显著性意义(P<0.05)。结论:精神分裂症患者存在免疫功能紊乱,氯氮平治疗可改善其免疫功能。     

脑梗死患者血清IL-6和TGF-β1的动态检测及其意义

目的探讨脑梗死患者发病后血清白细胞介素-6(IL-6)和转化生长因子β1(TGB-β1)的变化特点及其意义.方法采用双抗体夹心酶联免疫吸附试验(ELISA)法对31例脑梗死患者血清IL-6和TGF-β1进行动态检测.结果脑梗死患者血清IL-6在发病后第1天升至最高[(48.4±10.4)ng/L],随后逐渐下降,第3天和第7天分别下降至(38.2±9.6)ng/L和(31.4±6.8)ng/L,第7天仍显著高于对照组[(23.7±5.9)ng/L,P<0.01].轻、中、重三型脑梗死组间在同一时间段差异无显著性(P>0.05).在不同大小梗死灶间除发病后第1天组间差异有显著性外(F=4.13,P<0.05),其它时间段差异无显著性(P>0.05),其峰值与病情轻重无关(rs=0.186,P>0.05),而其与梗死灶大小呈正相关(rs=0.508,P<0.01);脑梗死患者血清TGF-β1在发病后第1天为最低,随后渐升,至第7天接近对照组[(42.1±8.2)μg/L],其变化与病情轻重或梗死灶大小无显著相关(P>0.05).结论结果提示IL-6和TGF-β1可能都参与了脑梗死的免疫-炎症反应;动态检测IL-6和TGF-β1有助于脑梗死的病情监测和治疗.     

补肾健脾活血方药对老年骨质疏松大鼠血清白细胞介素6的影响

背景近年来,细胞因子在骨质疏松中的作用备受关注,尤其血清白细胞介素6(IL-6)被认为是调节骨吸收的重要因子.目的观察实验性老年骨质疏松大鼠灌服补肾健脾活血方药后骨密度(BMD)和血清IL-6的变化. 设计以实验动物为研究对象的随机对照研究.单位解放军白求恩国际和平医院干部病房二科和一所中医学院的养生康复教研室.材料本实验于2003-05/2003-08在湖北中医学院实验动物中心完成,实验动物为30只Wistar大鼠,15月龄,雌雄各15只,购自华中科技大学同济医学院实验动物中心.方法将30只大鼠采用先分层再随机排列表法分为3组,即正常对照组、病理对照组、补肾健脾活血组.用地塞米松2.5 mg/kg体质量肌注大鼠、2次/周,连续6周,复制老年骨质疏松模型.正常对照组和病理对照组灌服生理盐水,补肾健脾活血组灌服补肾健脾活血方药.6周后用摘眼球法采血,离心取血清,采血后各组大鼠均离断右后肢完整取出右股骨.用排开丙酮法测各组BMD,用放免法测各组血清IL-6.主要观察指标BMD和血清IL-6水平.结果病理对照组的BMD明显低于正常对照组(P<0.01),血清IL-6水平明显高于正常对照组(P<0.01);补肾健脾活血组的BMD明显高于病理对照组(P<0.01),血清IL-6水平明显低于病理对照组(P<0.01).结论补肾健脾活血方药可减少IL-6分泌,降低血清IL-6水平,从而发挥抗骨丢失的作用.     

氯氮平治疗前后精神分裂症患者血浆及脑脊液中IL-6的变化

目的　研究氯氮平治疗精神分裂症前后患者血浆及脑脊液中IL 6的变化。方法　随机选取 30例住院患者为实验组 ,均符合《中国精神障碍分类与诊断标准》第 3版精神分裂症偏执型诊断标准 ,入组后单用氯氮平治疗 ;选取 2 0例健康志愿者作为对照组。采用酶联免疫吸附法测定对照组和实验组血浆及脑脊液中IL 6的浓度 ,并进行组间比较。结果　治疗前实验组血浆及脑脊液IL 6水平较对照组显著增高 ,两组比较有显著性差异 (P <0 .0 5 ) ;实验组治疗 6w后 ,IL 6水平较对照组显著增高 (P <0 .0 5 ) ;实验组症状基本缓解后血浆IL 6与治疗前比较无显著差异 (P >0 .0 5 )。结论　IL 6具有免疫增强作用 ,实验组血浆与脑脊液IL 6水平异常增高 ,提示精神分裂症患者存在免疫功能紊乱 ,可能是其精神活动障碍的病理生理机制之一     

动态观察蛛网膜下隙出血病人脑脊液白细胞介素-6含量变化的临床价值

目的探讨蛛网膜下隙出血(SAH)病人白细胞介素-6(IL-6)含量的变化及其临床意义.方法采用酶联免疫吸附法(ELISA)检测20例SAH患者在病程不同时期的脑脊液中IL-6含量,同时检测同期20例患非神经系统疾病病人作为对照.结果SAH患者在病程不同时期的脑脊液IL-6含量均显著高于对照组,均为P<0.001;SAH后第一日至第三日达峰值,第二周至第三周逐渐下降.SAH组6例脑血管痉挛患者的脑脊液IL-6含量明显高于同期无血管痉挛的SAH患者,P<0.01.结论SAH患者脑脊液中IL-6含量显著升高,SAH后脑血管痉挛患者IL-6水平明显高于无血管痉挛患者,动态观察SAH病人的IL-6水平有助于防治SAH后脑血管痉挛.     

Growth autonomy and tumorigenicity of interleukin 6-dependent B cells transfected with interleukin 6 cDNA

We introduced an IL-6 cDNA expression vector into a murine B cell line, the growth of which definitely required the presence of exogenous IL-6. The transfected cells secreted substantial amounts of IL-6, to which they themselves responded by proliferating without further requirement of exogenous IL-6. The proliferation was a direct function of cell density and was inhibitable by antibodies to IL-6, indicating the autocrine nature of the growth. The IL-6 cDNA-transfected cells displayed greatly enhanced tumorigenicity when inoculated into syngeneic and nude mice. Our data suggest that an IL-6 autocrine self stimulation confers on B cells a selective growth advantage and results in the induction of progression of the malignant state of B cells.     

Intracerebroventricular injection of interleukin 1 induces high circulating levels of interleukin 6

IL-1 is known to have a central role in the induction of acute-phase response, and some of its activities (including induction of some acute-phase proteins) were reported to be mediated by an induction of IL-6. Administration to rats of 200 ng of human rIL-1 by intracerebroventricular injection resulted in a more marked induction of circulating IL-6 than the same dose of IL-1 administered systemically (intravenously or intraperitoneally). Induction of serum IL-6 by centrally administered IL-1 was also observed in hypophysectomized or adrenalectomized rats, suggesting that activation of the hypothalamus-pituitary-adrenal axis is not essential for this effect of IL-1. IL-6 induction was also observed after pretreatment with indomethacin, indicating that the effect was dissociated from the pyrogenic activity of IL-1. Induction of IL-6 by a central action could represent a novel pathway in IL-1-induced acute-phase response.     

Antitumor activity of recombinant interleukin 6 in mice

IL-6 possesses multiple biologic activities that affect a broad range of cells including those directly involved in immune responses as well as cells important in the systemic response to infection or trauma. We now show that purified human rIL-6, when administered alone at relatively high doses that are comparable to therapeutic levels of IL-2, mediated substantial reductions in the number of pulmonary and hepatic micrometastases from four distinct syngeneic tumors. Unlike IL-2, IL-6 injections resulted in neither observable toxicity nor death of the treated mice at the dose regimens used. Host immunosuppression by sublethal total-body irradiation before the initiation of therapy prevented the IL-6 antitumor effect, thus suggesting that IL-6 acted through a radiosensitive host component rather than directly on the tumor itself. Moreover, the systemic administration of relatively low doses of IL-6 in combination with subtherapeutic doses of TNF to mice bearing an established weakly immunogenic, syngeneic tumor at a subcutaneous site resulted in marked tumor regression and cure rates. These studies represent the first demonstration of tumor regression mediated by recombinant IL-6 in vivo.     

Dominance of high-producing interleukin 6 and low-producing interleukin 10 and interferon gamma alleles in glucose-6-phosphate dehydrogenase-deficient trauma patients

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, a condition associated with malaria resistance, is a common genetic polymorphism. Decreased interleukin (IL)-10 production was demonstrated in vivo and in vitro in the African and Mediterranean forms of G6PD deficiencies. We hypothesized that low-producing IL-10 alleles are more abundant in the G6PD-deficient than nondeficient population. One hundred eleven men with African American ancestry were tested for G6PD deficiency (Type A-202/376) and for the cytokine gene promoter polymorphisms of IL-10 (-1082 G/A, -819 T/C, and -592 A/C), tumor necrosis factor (TNF)-alpha (-308 G/A), transforming growth factor (TGF)-beta1 (C/T codon 10 and C/G codon 25), IL-6 (-174 G/C), and interferon (IFN)-gamma (+874 A/T). There were no differences in the allele frequencies for TNF-alpha, IL-6, or TGF-beta1 between the G6PD-deficient and nondeficient population. In contrast, the low-producing IL-10 alleles (-592A) and low-producing IFN-gamma (+874A) allele frequencies were greater in G6PD-deficient than nondeficient samples (P = 0.035 and 0.009). Seventy-one percent of G6PD-deficient and 50% of nondeficient samples carried the high-producing IL-6(G) allele with low-producing IL-10(A) allele (P = 0.03). Furthermore, 95% of deficient and 81% of nondeficient samples carried the IL-6(G) allele together with low-producing IFN-gamma(A) allele (P = 0.017). These investigations indicate a predominant presence of high-producing IL-6 alleles together with low-producing IL-10 and IFN-gamma alleles in individuals with ancestry from malaria-endemic regions. The frequency of low-producing IL-10 genotypes is greater in the G6PD-deficient compared with nondeficient patients. The fact that these genetic differences are preserved in the current African American G6PD-deficient population indicates their potential role in pathophysiological processes in the absence of the selective pressure caused by tropical diseases.     

Defective inflammatory response in interleukin 6-deficient mice

Systemic and localized inflammation elicit a number of host responses which include fever, cachexia, hypoglycemia, and major changes in the concentration of liver plasma proteins. Interleukin 6 (IL-6) is considered an important mediator of the inflammatory response, together with IL-1 and tumor necrosis factor alpha (TNF-alpha). The purpose of this study was to unequivocally determine the role of IL-6 in these phenomena making use of IL-6-deficient mice that we have recently generated by gene targeting. We report here that in the absence of IL- 6, mice are unable to mount a normal inflammatory response to localized tissue damage generated by turpentine injection. The induction of acute phase proteins is dramatically reduced, mice do not lose body weight and only suffer from mild anorexia and hypoglycemia. In contrast, when systemic inflammation is elicited through the injection of bacterial lipopolysaccharide (LPS), these parameters are altered to the same extent both in wild-type and IL-6-deficient mice, demonstrating that under these conditions IL-6 function is dispensable. Moreover, we show that LPS-treated IL-6-deficient mice produce three times more TNF-alpha than wild-type controls, suggesting that increased TNF-alpha production might be one of the compensatory mechanisms through which a normal response to LPS is achieved in the absence of IL-6. We also show that corticosterone is normally induced in IL-6-deficient mice, demonstrating that IL-6 is not required for the activation of the hypothalamic-pituitary-adrenal axis. Our results reinforce the idea that different patterns of cytokines are involved in systemic and localized tissue damage, and identify IL-6 as an essential mediator of the inflammatory response to localized inflammation.     

Proliferating or interleukin 1-activated human vascular smooth muscle cells secrete copious interleukin 6.

The cells that make up blood vessel walls appear to participate actively in local immune and inflammatory responses, as well as in certain vascular diseases. We tested here whether smooth muscle cells (SMC) can produce the important inflammatory mediator IL6. Unstimulated SMC in vitro elaborated 5 X 10(3) pg recIL6/24h (i.e., biological activity equivalent to 5 X 10(3) pg recombinant IL6 (recIL6), as determined in B9-assay with a recIL6 standard). Several pathophysiologically relevant factors augmented IL6 release from SMC including 10 micrograms LPS/ml (10(4) pg recIL6), 10 ng tumor necrosis factor/ml (4 X 10(4) pg recIL6), and most notably 10 ng IL1/ml (greater than or equal to 3.2 X 10(5) pg recIL6). Production of IL6 activity corresponded to IL6 mRNA accumulation and de novo synthesis. SMC released newly synthesized IL6 rapidly, as little metabolically labeled material remained cell-associated. In supernatants of IL1-stimulated SMC, IL6 accounted for as much as 4% of the secreted proteins. In normal vessels SMC seldom divide, but SMC proliferation can occur in hypertension or during atherogenesis. We therefore tested the relationship between IL6 production and SMC proliferation in response to platelet-derived growth factor (PDGF) in vitro. Quiescent SMC released scant IL6 activity, whereas PDGF (1-100 ng/ml) produced concentration-dependent and coordinate enhancement of SMC proliferation and IL6 release (linear regression of growth vs. IL6 release yielded r greater than 0.9). IL6 itself neither stimulated nor inhibited SMC growth or IL6 production. Intact medial strips studied in short-term organoid culture produced large quantities of IL6, similar to the results obtained with cultured SMC. These findings illustrate a new function of vascular SMC by which these cells might participate in local immunoregulation and in the pathogenesis of various important vascular diseases as well as in inflammatory responses generally.     

Ceramide induces interleukin 6 gene expression in human fibroblasts

We previously reported that ceramide, the immediate product of sphingomyelin hydrolysis, increases in response to interleukin (IL)-1 beta and plays a role in modulating IL-1 beta-mediated prostaglandin E2 production and cyclooxygenase gene expression in human fibroblasts (Ballou, L. R., C. P. Chao, M. A. Holness, S. C. Barker, and R. Raghow. 1992. J. Biol. Chem. 267:20044-20050). Here we describe the effects of ceramide in another IL-1 beta-mediated process in these cells, the induction of IL-6 production. We found that submicromolar concentrations of C2-ceramide induced IL-6 gene expression and protein production as effectively as IL-1 beta. Both D-erythro-C2-ceramide (a cell-permeable analogue of natural ceramide) and D-threo-C2-ceramide were potent inducers of IL-6 production, while neither L isomer of ceramide was effective. Compared with IL-1 beta-induced IL-6 production, cells treated with ceramide or exogenous sphingomyelinase induced 82 and 50% of maximal IL-1 beta-induced IL-6 levels by 6 h, respectively; by 24 h all three treatments induced similar levels of IL- 6 production. Ceramide-induced IL-6 messenger RNA could be detected within 1 h of treatment and reached maximal levels by 24 h. These findings suggest that ceramide may play a role in the regulation of IL- 6 gene expression.     

Association between nucleated red blood cells in blood and the levels of erythropoietin, interleukin 3, interleukin 6, and interleukin 12p70

The appearance of nucleated red blood cells (NRBC) in the circulation is associated with a variety of severe diseases, and indicates a relatively poor prognosis. Whether a malfunction of the bone marrow leads to this phenomenon is as unknown as the possible role that cytokines could play in this process. We analyzed erythropoietin, interleukin (IL)-3, IL-6, and IL-12p70 in the blood of 301 patients with circulating NRBCs. Two hundred fifty NRBC-negative patients served as controls. Multiple logistic regression revealed a significant association between the appearance of NRBCs in the blood and erythropoietin (odds ratio, 1.017; 95% confidence limits, 1.007-1.027; P < 0.001), IL-3 (odds ratio, 1.293; 95% confidence limits, 1.180-1.417; P < 0.001), IL-6 (odds ratio, 1.138; 95% confidence limits, 1.016-1.275; P < 0.05), and age (odds ratio, 1.019; 95% confidence limits, 1.009-1.030; P < 0.001), respectively. Gender and IL-12p70 were not significantly associated with the appearance of NRBC in the blood. To estimate the RBC production in the bone marrow, the increase in the reticulocyte concentration in blood was measured. The reticulocyte concentration in NRBC-positive patients was 69 +/- 2/nL, which was significantly higher than in NRBC-negative patients (60 +/- 2/nL; P < 0.01). Taken together, NRBC could be a marker that sums up hypoxic and inflammatory injuries. Thus, generally, the appearance of NRBC in blood is a valid parameter to identify patients at high mortal risk. Moreover, the increased number of reticulocytes in the blood of NRBC-positive patients may indicate that the appearance of NRBC is not associated with disturbed bone marrow function as far as the erythropoiesis is concerned.     

Synergism of BSF-2/interleukin 6 and interleukin 3 on development of multipotential hemopoietic progenitors in serum-free culture

We investigated the effects of B cell stimulatory factor 2/interleukin 6 (BSF-2/IL-6) on the development of murine hemopoietic progenitors using serum-containing culture and serum-free culture. In serum-containing culture, BSF-2 mainly supported multipotential blast cell colonies from spleen cells of normal and 5-fluorouracil (5-FU)-treated mice. In serum-free culture, no colony growth was seen in the presence of BSF-2. Addition of BSF-2 to the serum-free culture containing IL-3 resulted in a significant increase in the number of colonies formed from multipotential progenitors in spleen cells and bone marrow cells of 5-FU-treated mice, whereas no effects were seen on the number of single or oligolineage colonies formed by the spleen cells of normal mice. These results suggested that BSF-2 and IL-3 act synergistically on the multipotential progenitors but not on the maturer progenitors. When BSF-2 was added to a culture containing low concentrations of IL-3 (1 U/ml, 4 U/ml), which had little effect on colony formation, the number of total colonies formed by the spleen cells and bone marrow cells of 5-FU-treated mice increased significantly. The combination of BSF-2 and 40 U/ml of IL-3 resulted in a significant enlargement of GMM colonies. Thus, BSF-2 appears to enhance the sensitivity of multipotential hemopoietic progenitors to IL-3.