A Review of the New Cytokines: IL-4, IL-6, IL-11, and IL-12

The interleukins function as intercellular hormones, possessing the ability to alter the activity of a target cell population. Interleukin-4, secreted by activated T-cells, has shown antitumor activity in vitro against multiple myelomas, lymphoma, chronic myelomonocytic leukemia, and some solid tumors. Early promising clinical studies have shown the efficacy of IL-4 in decreasing the malignant lymphocyte count and in normalizing hematologic parameters in patients with CLL and in inducing transient clinical responses in patients with non-Hodgkin's lymphoma. Interleukin-6 possesses immunomodulating properties including enhancement of NK cell activity and induction of cytotoxic T-cell activity. IL-6 has shown antitumor activity in mice injected with weakly immunogenic syngeneic tumors and has been shown to inhibit in vitro human breast carcinoma and leukemia/lymphoma proliferation through a direct tumor inhibitory effect. Clinical studies investigating the antitumor activity of IL-6 are currently in phase II clinical trials. IL-6 and IL-11 have demonstrated thrombopoietic enhancing activity in primate models and early clinical trials. These agents have a potential application in ameliorating the thrombocytopenia associated with myeloablative chemotherapy. Yet to enter clinical trials, IL-12 has been shown to enhance the lytic activity of nonspecific NK/LAK cells and appears to be more efficient than IL-2 or IFN's in enhancing NK cytotoxicity. IL-12 has also been shown to enhance specific allogeneic human CTL responses and to induce the secretion of IFN-gamma from both resting and activated T and NK cells. In summary, these interleukins are now promising agents under investigation as effective treatment strategies in the oncologic setting.     

雷公藤多苷对白塞病患者血清细胞因子水平的影响

目的 探讨雷公藤多苷对白塞病患者血清细胞因子IL-4、IL-6、IL-8、IL-10水平的影响,进而从分子生物学水平探讨雷公藤多苷对白塞病的治疗作用及其可能的机制。方法 收集济宁医学院附属医院2007年6月至2009年6月门诊就诊的初治白塞病患者30例,给予雷公藤多苷片30 mg/d,疗程3个月,对照组为健康体检者30例。采用放免法测定白塞病患者接受雷公藤多苷治疗前后,以及对照组的血清细胞因子IL-4、IL-6、IL-8、IL-10的水平。并结合血沉、C-反应蛋白及临床表现等情况进行分析。结果 （1）白塞病患者治疗前血清IL-6、IL-8水平明显高于正常对照组（P＜0.05）, IL-4、IL-10水平较正常对照组无明显变化（P＞0.05）。（2）雷公藤多苷治疗3个月后患者血清IL-6、IL-8水平较治疗前明显减低（P＜0.05）, IL-4、IL-10水平较治疗前明显升高（P＜0.05）。（3）30例接受雷公藤多苷治疗的患者中,显效10例,有效16例,无效4例,有效率86.7%,治疗3个月后患者血沉、C-反应蛋白水平均较治疗前明显降低（P＜0.05）。结论 （1）白塞病患者血清IL-4、IL-6、IL-8、IL-10水平的失衡可能与其发病有关;（2）雷公藤多苷可有效调节白塞病患者血清IL-4、IL-6、IL-8、IL-10的水平,从而发挥其治疗作用。     

Inflammatory cytokines (IL-4, IL-5 and IL-13)]

The polarized Th2 cells play an important role in the pathogenesis of atopic asthma as well as in the induction of airway inflammation. Th2 cytokines, such as IL-4, IL-5 and IL-13, are pivotal in regulating the allergic phenotype, the IgE response or the inflammatory cell-mediated function. Selective inhibition of Th2 cytokines by pharmacologic agents, including anti-cytokine blocking antibody, cytokine mutant and soluble cytokine receptor, will contribute to asthma therapy. Strategies based on blocking key signaling cytokines are also discussed.     

血清IL-12、IL-10及IL-18与肺结核的相关性研究

目的探讨肺结核患者对血清白细胞介素-12(IL-12)、白细胞介素-10(IL-10)和白细胞介素-18(IL-18)表达的影响,并分析血清IL-12、IL-10和IL-18与肺结核的相关性。方法随机选择首次复治肺结核80例为复治组,初治肺结核120例为初治组,体检健康100例为对照组;分别检测三组的血IL-12、IL-10和IL-18水平,并比较三组血清IL-12、IL-10和IL-18水平与临床意义。结果治疗前,复治组血清IL-12、IL-10和IL-18水平均明显高于初治组、对照组,差异均有统计学意义(P<0.05);初治组血清IL-12、IL-10和IL-18水平均与对照组比较,差异均有统计学意义(P<0.05);治疗后,三组的血清IL-12、IL-10和IL-18水平均比较,差异均无有统计学意义(P>0.05)。结论 IL-12、IL-10和IL-18参与了肺结核的发生、发展,检测相关血清炎症因子水平有助于对肺结核疾病变化过程和治疗功效的评估。     

前列腺素E1对ARDS病人TNF-α IL-1β IL-6 IL-8的影响

目的 观察PGE1对急性呼吸窘迫综合征(RDS)病人细胞因子TNF-α、IL-1β、IL-6、IL-8的影响,探讨PGE1治疗ARDS的可能作用机制。方法 61例ARDS病人随机分为PGE1治疗组和对照组,应用放射免疫技术测定ARDS机械通气即刻、48h、5d时细胞因子TNF-α、IL-1β、IL-6、IL-8的水平。结果 PGE1治疗组在ARDS机械通气48h、5d时细胞因子TNF-α、IL-1β、IL-6、IL-8活性比对照组显著降低(P<0.01)。结论 PGE1可降低ARDS病程细胞因子活性。     

系统性红斑狼疮患者血清可溶性细胞间粘附分子-1、L-选择素、细胞因子的变化及意义

目的探讨系统性红斑狼疮（SLE）患者血清可溶性细胞间粘附分子-1（sICAM-1）、L-选择素、白细胞介素（IL）-2、IL-6、IL-8和IL-10水平的变化及其致病意义。方法采自24例SLE患者的血清标本分别用酶联免疫吸附试验（ELISA）检测sICAM-1和L-选择素;用放射免疫检测法（RIA）检测IL-2、IL-6、IL-8和IL-10;另以20名健康志愿者作为对照。结果SLE患者血清sICAM-1、L-选择素、IL-6及IL-2/IL-10比值显著高于对照组（P〈0.05）,IL-2无明显变化,IL-8水平稍高于对照组,但差异无统计学意义（P〉0.05）。结论SLE患者sICAM-1、L-选择素和IL-6表达增加,而IL-10表达减少,提示免疫紊乱、促炎与抗炎细胞因子失平衡参与了SLE的发病过程。     

系统性红斑狼疮患者血清可溶性细胞间粘附分子-1、L-选择素、细胞因子的变化及意义

目的探讨系统性红斑狼疮(SLE)患者血清可溶性细胞间粘附分子-1(sICAM-1)、L-选择素、白细胞介素(IL)-2、IL-6、IL-8和IL-10水平的变化及其致病意义。方法采自24例SLE患者的血清标本分别用酶联免疫吸附试验(ELISA)检测sICAM-1和L-选择素;用放射免疫检测法(RIA)检测IL-2、IL-6、IL-8和IL-10;另以20名健康志愿者作为对照。结果SLE患者血清sICAM-1、L-选择素、IL-6及IL-2/IL-10比值显著高于对照组(P<0.05),IL-2无明显变化,IL-8水平稍高于对照组,但差异无统计学意义(P>0.05)。结论SLE患者sICAM-1、L-选择素和IL-6表达增加,而IL-10表达减少,提示免疫紊乱、促炎与抗炎细胞因子失平衡参与了SLE的发病过程。     

Methylprednisolone prevents inflammatory reaction occurring during cardiopulmonary bypass: effects on TNF-alpha, IL-6, IL-8, IL-10

OBJECTIVE: This study examined the correlation between tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-6 and IL-8, IL-10 and methylprednisolone pretreatment. METHODS: This is a prospective, randomized and double-blinded study. Sixty patients undergoing coronary artery bypass grafting (CABG) were randomized to receive either intravenous methylprednisolone (n = 30, Group M) or intravenous placebo (n = 30, Group S). The patients received intravenously either 30 mg/kg methylprednisolone (Group M) or placebo (Group S) 10 min before and after cardiopulmonary bypass (CPB). In an intensive care unit (ICU), four additional doses were given at 6-hourly intervals. Blood samples for the measurements of TNF-alpha, IL-6, IL-8 and IL-10 were obtained before induction of anaesthesia (T0 = control value), after induction (T1), before starting CPB (T2), after aortic declamping (T3), at the end of CPB (T4) and 6 hours (T5), 12 hours (T6) and 24 hours (T7) after skin closure. Creatine kinase (CK) and creatine kinase isoenzyme MB (CK-MB) were evaluated at the following intervals: T0, T5, T6 and T7. RESULTS: When compared with the control value, TNF-alpha, IL-6 and IL-8 significantly increased in Group S and Group M (p < 0.05), but these values were significantly greater in Group S than in Group M (p < 0.05). In comparison with the control value, IL-10 increased in both groups (p < 0.05), but was significantly greater in Group M than in Group S (p < 0.05). CK and CK-MB were increased in both groups in postoperative values compared to control values. In Group S, CK and CK-MB levels were significantly lower than in Group M (p < 0.05). CONCLUSION: In this study, we have found that preoperative administration of methylprednisolone has decreased TNF-alpha, IL-6 and IL-8 release, and increased the perfusing IL-10 levels after CPB. Thus, methylprednisolone may decrease the inflammatory response during the CPB procedure.     

血清IL-6、IL-10及IL-12在膀胱癌中表达及临床意义

目的探讨检测膀胱癌患者血清IL-6、IL-10、IL-12水平的意义。方法应用酶联免疫法测定膀胱癌和健康者血清IL-6、IL-10、IL-12的含量，并分析其与膀胱癌临床病理分期的关系。结果膀胱癌组血清IL．6显著高于对照组（P〈0.01），且随着肿瘤临床病理分期的进展而逐渐升高：而血清IL-10和IL-12的含量显著低于对照组（P〈O．01）。结论膀胱癌患者血清细胞因子IL-6、IL-10和1L-12的变化可能与肿瘤的生长及机体的抗肿瘤免疫功能受损有关。     

Impact of weight loss on circulating IL-1, IL-6, IL-8, TNF-alpha, VEGF-A, VEGF-C and midkine in gastroesophageal cancer patients

OBJECTIVE: Proinflammatory cytokines are involved in cancer-related weight loss, but the involvement of VEGF-A, VEGF-C, IL-8 and midkine in gastroesophageal cancer patients remains unknown. DESIGN AND METHODS: Serum IL-1, IL-6, IL-8, TNF-alpha, VEGF-A, VEGF-C, and midkine were evaluated in 96 cancer patients and 42 controls using ELISAs and were related to the occurrence of weight loss, patient's age, gender and BMI, cancer TNM status and blood cell counts. RESULTS: All cytokines were elevated in cancer patients with further up-regulation of IL-6, IL-8, midkine and VEGF-A in cachexia. Underweight, midkine and VEGF-A were found independent indicators of weight loss. Primary tumor seems to be a major source of pro-cachectic cytokines, yet neutrophils and platelets also contribute to cytokine elevation. CONCLUSIONS: IL-6 and IL-8, and probably midkine and VEGF-A, appear to participate in the development of cancer-related cachexia in gastroesophageal malignancies, although a detailed mechanism underlying cytokine involvement needs to be elucidated.     

IL-13 IL-18 LTB-4在哮喘患者中的变化研究

目的探讨白细胞介素-13(IL-13)、白细胞介素-8(IL-8)、白三烯(LTB-4)在支气管哮喘患者中的变化。方法选择健康者、哮喘急性发作者、临床缓解者各36例。取静脉血,用酶联免疫吸附试验测定血清中IL-13、IL-18、LTB-4水平,并进行统计学分析。结果哮喘患者血清IL-13、IL-18、LTB-4水平急性发作者显著高于缓解者,且两组均显著高于健康对照组,差异有统计学意义(P<0.01)。结论 IL-13、IL-18、LTB-4参与了哮喘慢性炎性反应的形成,检测IL-13、IL-18、LTB-4可评估哮喘病情发展状态,指导临床治疗。     

CCl4攻击小鼠致肝纤维化血清IL-4、IL-6、IL-8表达的影响

目的：观察CCl4攻击小鼠致肝纤维化血清IL-4、IL-6、IL-8的动态变化规律及其表达的影响。方法：将小鼠分为4组：雌、雄性小鼠对照组、雌、雄性小鼠体积分数为30%四氯化碳花生油组（皮下注射）。用ELISA及酶标仪方法检测小鼠血清IL-4、IL-6、IL-8的含量及肝脏、脾脏的表达情况。结果：CCl4攻击可使小鼠血清IL-6、IL-8含量增加,IL-4的表达进一步减少。结论：CCl4可能通过攻击小鼠IL-4、IL-6、IL-8的表达参与抗炎反应过程,细胞因子在肝纤维化发病过程中起重要的作用。检测血清IL-4、IL-6、IL-8浓度的变化可作为了解其与肝纤维化的关系。     

Tuning sensitivity to IL-4 and IL-13: differential expression of IL-4Ralpha, IL-13Ralpha1, and gammac regulates relative cytokine sensitivity

Interleukin (IL)-4 and -13 are related cytokines sharing functional receptors. IL-4 signals through the type I (IL-4Rα/common γ-chain [γc]) and the type II (IL-4Rα/-13Rα1) IL-4 receptors, whereas IL-13 utilizes only the type II receptor. In this study, we show that mouse bone marrow–derived macrophages and human and mouse monocytes showed a much greater sensitivity to IL-4 than to IL-13. Lack of functional γc made these cells poorly responsive to IL-4, while retaining full responsiveness to IL-13. In mouse peritoneal macrophages, IL-4 potency exceeds that of IL-13, but lack of γc had only a modest effect on IL-4 signaling. In contrast, IL-13 stimulated greater responses than IL-4 in fibroblasts. Using levels of receptor chain expression and known binding affinities, we modeled the assemblage of functional type I and II receptor complexes. The differential expression of IL-4Rα, IL-13Rα1, and γc accounted for the distinct IL-4–IL-13 sensitivities of the various cell types. These findings provide an explanation for IL-13's principal function as an “effector” cytokine and IL-4's principal role as an “immunoregulatory” cytokine.     

白细胞介素4、白细胞介素8、白细胞介素10在哮喘和慢性阻塞性肺疾病发病中的作用

目的:探讨外周血白细胞介素4(IL-4)、白细胞介素8(IL-8)、白细胞介素10(IL-10)在哮喘和慢性阻塞性肺疾病(COPD)发病中的作用。方法:采用双抗体夹心酶联免疫吸附法(ELISA)分别检测急性发作期和缓解期哮喘患者各50例(哮喘组)、急性加期和缓解期COPD患者各50例(COPD组)及健康志愿者50例(健康对照组)血清中IL-4、IL-8、IL-10的水平。结果:哮喘组急性发作期IL-4、IL-8水平均显著高于缓解期(P<0.01),且2期均显著高于正常对照组(P<0.01);哮喘组急性发作期IL-10水平显著低于缓解期(P<0.01),且2期均显著低于健康对照组(P<0.01)。COPD组急性加重期IL-4、IL-8水平均显著高于缓解期(P<0.01),且2期均显著高于健康对照组(P<0.01)。哮喘组急性发作期IL-10水平显著低于缓解期(P<0.01),且2期均显著低于健康对照组(P<0.01)。哮喘急性加重期IL-4水平显著高于COPD急性加重期(P<0.01);COPD急性加重期IL-8水平高于哮喘急性发作期(P<0.01);哮喘急性发作期IL-10水平显著低于COPD急性发作期(P<0.01)。结论:IL-4、IL-8、IL-10均参与了哮喘和COPD的气道炎性反应,IL-4、IL-8是促炎因子,而IL-10是抑炎因子。IL-4在哮喘的气道炎症形成中起重要的作用。而IL-8、IL-10为COPD的主要炎症因子。     

Divergence of IL-1, IL-18, and cell death in NLRP3 inflammasomopathies

The inflammasome is a cytoplasmic multiprotein complex that promotes proinflammatory cytokine maturation in response to host- and pathogen-derived signals. Missense mutations in cryopyrin (NLRP3) result in a hyperactive inflammasome that drives overproduction of the proinflammatory cytokines IL-1β and IL-18, leading to the cryopyrin-associated periodic syndromes (CAPS) disease spectrum. Mouse lines harboring CAPS-associated mutations in Nlrp3 have elevated levels of IL-1β and IL-18 and closely mimic human disease. To examine the role of inflammasome-driven IL-18 in murine CAPS, we bred Nlrp3 mutations onto an Il18r-null background. Deletion of Il18r resulted in partial phenotypic rescue that abolished skin and visceral disease in young mice and normalized serum cytokines to a greater extent than breeding to Il1r-null mice. Significant systemic inflammation developed in aging Nlrp3 mutant Il18r-null mice, indicating that IL-1 and IL-18 drive pathology at different stages of the disease process. Ongoing inflammation in double-cytokine knockout CAPS mice implicated a role for caspase-1–mediated pyroptosis and confirmed that CAPS is inflammasome dependent. Our results have important implications for patients with CAPS and residual disease, emphasizing the need to explore other NLRP3-mediated pathways and the potential for inflammasome-targeted therapy.     

慢性肝病患者血清IL-6、IL-8、IL-10 和TNF-α的水平变化及意义

目的：探讨慢性肝病患者血清白细胞介素-6（IL-6）、白细胞介素-8（IL-8）、白细胞介素-10（IL-10）和肿瘤坏死因子（TNF-α）在肝病发展过程中的含量变化及临床意义.方法：用放射免疫分析检测105例慢性肝病患者和32例正常对照组血清IL-6、IL-8、IL-10、TNF-α的水平.结果：各组慢性肝病患者血清IL-6、IL-8、TNF-α含量明显高于正常对照组（P＜0.05）,而血清IL-10明显低于正常对照组（P＜0.01）,肝病患者各组间细胞因子水平比较也有显著性差异（P＜0.01）.结论：细胞因子IL-6、IL-8、IL-10和TNF-α在肝病发展过程中相互作用,联合检测其水平的变化对探讨慢性肝病的诊断、治疗和预后具有重要意义.     

急性移植物抗宿主病病人血清IL-2、IL-8、IL-10及TNF-α水平变化的研究

为了探讨细胞因子IL-2、TNF—α、IL-10、IL-8在异基因造血干细胞移植后aGVHD发病中的作用，观察33例Allo-HSCT患者aGVHD的发病情况。aGVHD的诊断主要依据临床表现，部分病例还依据皮肤、肠粘膜活检的病理学变化。移植前后定期采集患者血清，采用放射免疫法检测细胞因子IL-2、TNF—α、IL-10、IL-8的浓度的变化。结果发现，异基因造血干细胞移植后33例患者均获得造血功能重建，13例发生aGVHD，其中8例Ⅰ度aGVHD，5例Ⅱ-Ⅳ度aGVHD。IL-2、TNF—α水平在aGVHD阳性组明显高于aGVHD阴性组，而IL-10的水平在aGVHD阳性组明显低于aGVHD阴性组，IL-8水平的变化无统计学意义。结论：细胞因子IL-2、TNF—α在临床aGVHD的发病中起重要的正向调节作用，定期检测患者血清的IL-2、TNF—α水平有助于预测aGVHD的发生。