白细胞介素-17与白细胞介素-35在自身免疫性疾病中的研究进展

自身免疫性疾病是免疫耐受性破坏的结果,最终导致组织损伤,但病因尚未阐明。辅助性T细胞(Th17)、调节性T细胞(Treg)、Treg/Th17失衡及其相关细胞因子与自身免疫性疾病的发生发展密切相关。白细胞介素(IL)-17主要由Th17分泌,具有促炎效应,参与各种自身免疫性疾病发生发展。IL-35是IL-12家族的一种新型细胞因子,主要由Treg产生,具有免疫负性调节作用,是Th17/Treg相关的重要细胞因子。本文就IL-17与IL-35的功能、效应机制及其在自身免疫性疾病中的作用等进行综述,以为该病的治疗提供理论基础。     

白细胞介素-4、白细胞介素-8、白细胞介素-9在支气管哮喘患儿血清中的表达及临床意义

目的 观察白细胞介素(IL)-4、IL-8、IL-9在支气管哮喘患儿血清中的表达,并探讨其临床意义.方法 选取支气管哮喘急性发作期、临床缓解期患儿各43例,分别设为发作组和缓解组,另选取同期体检健康儿童37例作为对照组,检测所有儿童的血清IL-4、IL-8、IL-9水平.结果 IL-4、IL-8、IL-9在对照组、缓解组、发作组儿童血清中的表达水平均呈递增趋势,组间比较均有显著差异(P＜0.01).结论 血清IL-4、IL-8、IL-9水平与支气管哮喘的发生、发展过程密切相关,临床可作为支气管哮喘病情进展的参考指标.     

毛细支气管炎患儿血清白细胞介素-4、白细胞介素-8水平的临床意义及对策

目的通过检测毛细支气管炎(以下简称毛支)患儿血清白细胞介素-4(IL-4)、白细胞介素-8(IL-8)水平,研究其在发病中的临床意义及探讨相应的治疗对策。方法研究对象为106例住院毛支患儿(毛支组),随机选择其中40例为红霉素治疗组,31例为常规治疗组;另选34例正常小儿为对照组。采用双抗体夹心酶联免疫吸附法(ELISA),分别在毛支患儿急性期(入院当时)及恢复期(住院7 d后)检测血清IL-4、IL-8水平,正常小儿一次性检测。各组进行比较,并观察治疗7 d有效率。结果毛支组急性期血清IL-4水平与恢复期及对照组比较差异均无统计学意义(P>0.05);毛支组急性期IL-8水平高于恢复期,差异有统计学意义(P<0.05),与对照组比较,差异有统计学意义(P<0.05);红霉素治疗组恢复期血清IL-8水平低于常规治疗组,差异有统计学意义(P<0.05);红霉素治疗组的7天有效率高于常规治疗组(P<0.05)。结论 IL-4可能未参与毛支的发病,嗜酸性粒细胞并不是引起毛支的主要细胞,毛支可能不是过敏性炎症;IL-8参与毛支的病理过程,毛支气道炎症细胞可能以中性粒细胞为主;红霉素具有抗炎和免疫调节作用,可用于佐治毛支。     

Helicobacter pylori infection enhances mucosal interleukin-1β, interleukin-6, and the soluble receptor of interleukin-2

It is thought thatHelicobacter pylori colonization of the gastric mucosa might stimulate the production of several cytokines, which might trigger and maintain the gastric inflammation associated withHelicobacter pylori infection. In the present study we evaluated interleukin-1β, interleukin-6, and the soluble receptor of interleukin-2 both in mucosal homogenates and in the sera ofHelicobacter pylori-infected (39 cases) and uninfected (40 cases) patients to investigate whether there was any relationship between variations in cytokines and (1) the severity ofHelicobacter pylori-associated gastritis or (2) CagA-positiveHelicobacter pylori strains. Mucosal, but not serum levels of interleukins-1 and-6 and interleukin-2 receptor were significantly higher in infected than uninfected patients, Serum levels ofHelicobacter pylori antibodies were significantly higher in infected than uninfected patients, These levels correlated with mucosal interleukin-1β. The degree of antral or body inflammatory grade was higher in infected than in uninfected patients; cytokines levels were higher in patients with high-grade gastritis, most of whom wereHelicobacter pylori positive. Patients infected with CagA-positive strains also had higher levels of interleukin-1β, but not of interleukin-2 receptor or interleukin-6. In conclusion,Helicobacter pylori infection results in a local increase in interleukins-1β and-6 and interleukin-2 receptor associated with high-grade mucosal inflammation. Interleukin-1β seems to favor anti-Helicobacter pylori antibody production, and mucosal levels are enhanced mainly in patients infected with cytotoxicHelicobacter pylori strains.     

白细胞介素-18和白细胞介素-12在儿童1型糖尿病酮症酸中毒中的作用

目的探讨白细胞介素-18(IL-18)、白细胞介素-12(IL-12)和干扰素-γ(INF-γ)在儿童1型糖尿病酮症酸中毒(DKA)中的作用。方法采用酶联免疫吸附(ELISA)方法检测61例儿童1型糖尿病(T1DM)患儿(其中28例伴DKA,33例无DKA)和30例正常对照者IL-18、IFN-γ和IL-12的血清水平。结果(1)T1DM患儿中血清IL-18水平明显比对照组高[(691．99±381．42) pg/ml vs(310．02±265．32)pg/ml,P=0．03],而两组间IFN-γ和IL-12水平则无差别。(2)DKA组患儿中IL-18和IFN-γ血清水平明显高于无DKA组[(759．25±353．82)pg/ml vs(634．93±399．79)pg/ ml,P=0．001和(9．35±8．06)pg/ml vs(5．21±6．47)pg/ml,P=0．044],而两组间IL-12血清水平则无差别。(3)IL-18和IFN-γ呈相关趋势,而与IL-12正相关。结论DKA患儿IL-18和IFN-γ血清水平明显升高,提示其可能在DKA的发生、发展中起重要作用。     

Lentiviral-mediated interleukin-4 and interleukin-13 RNA interference decrease airway inflammation and hyperresponsiveness

Interleukin (IL)-4 and IL-13 are two key cytokines released from activated T helper type 2 (Th2) cells and strongly associated with asthma and allergic disease. We applied silencing of the IL-4 and IL-13 gene expression by RNA interference delivered by a lentiviral vector to evaluate the therapeutic role of IL-4 and IL13 short hairpin RNAs (shRNAs) in a murine model of asthma. Mice were sensitized with ovalbumin (OVA), and one treatment of IL-4 and IL-13 shRNA lentiviral vector (Lenti-si-IL-4 and Lenti-si-IL-13) was instilled intratracheally 48?hr before challenge. After three challenges of OVA antigen, mice were assessed for airway inflammation and hyperresponsiveness. With infection of Lenti-si-IL-4 and Lenti-si-IL-13 in EL-4 cells, both RNA and protein expressions of IL-4 and IL-13 were obviously abrogated. Furthermore, intratracheal instillation of Lenti-si-IL-4 and Lenti-si-IL-13 in OVA-immunized mice resulted in a strong inhibition of local IL-4 and IL-13 cytokine release. Treatment with Lenti-si-IL-4 and Lenti-si-IL-13 successfully alleviated OVA-induced airway eosinophilia and Th2 cell cytokine release. Finally, to determine airway hyperresponsiveness by enhanced pause and pulmonary resistance in noninvasive and invasive body plethysmography, we found that administration of Lenti-si-IL-4 and Lenti-si-IL-13 markedly decreased airway hyperresponsiveness in OVA-immunized mice. These results suggest that inhibition of IL-4 and IL-13 gene expression by shRNA lentiviral vector markedly inhibits antigen-induced airway inflammation and hyperresponsiveness in mice.     

Regulation of T helper type 2 cell immunity by interleukin-4 and interleukin-13

Type 2 cytokine responses are typical of immune reactions to parasitic helminth infections, allergies, and asthma, and are characterised by the production of the cytokines interleukin (IL)-4, IL-5, IL-9, and IL-13 by subsets of T helper type 2 (Th2) cells. These cytokines form a complex network of molecular and cellular interactions that mediate protective immunity to worm infection, but also induce inappropriate inflammatory responses to allergic challenge. Although considerable attention has been given to the roles played by IL-4 in Th2 responses, the identification of the related cytokine IL-13 has led to a re-evaluation of how these two molecules combine in the generation of Th2 immunity. Recent reports have highlighted that in certain challenges, IL-4 and IL-13 act in combination to ensure the rapid onset of a Th2-like response. However, these studies have also identified specific responses that are attributable to the individual cytokines. For example, IL-13 appears to play a more dominant role than IL-4 in the expulsion of certain gastrointestinal parasites. In contrast, following schistosome infection, IL-13 induces a detrimental hepatic fibrosis, while IL-4 protects against endotoxemia. These results emphasise the complexity of the cytokine network, and highlight the care that needs to be taken when designing therapeutic intervention.     

Interferon-gamma differentially regulates interleukin-12 and interleukin-10 production in leprosy.

The ability of monocytes to influence the nature of the T cell response to microbial pathogens is mediated in part by the release of cytokines. Of particular importance is the release of IL-12 and IL-10 by cells of the monocyte/macrophage lineage upon encountering the infectious agent. IL-12 promotes cell mediated immunity (CMI) to intracellular pathogens by augmenting T-helper type 1 responses, whereas IL-10 downregulates these responses. The ability of IFN-gamma to modulate the balance between IL-12 and IL-10 production was examined by studying leprosy as a model. In response to Mycobacterium leprae stimulation, IFN-gamma differentially regulated IL-12 and IL-10 production resulting in upregulation of IL-12 release and downregulation of IL-10 release. Furthermore, we determined that the mechanism by which IFN-gamma downregulates IL-10 was through the induction of IL-12. The data suggest a model of lymphocyte-monocyte interaction whereby the relative presence or absence of IFN-gamma in the local microenvironment is a key determinant of the type of monocyte cytokine response, and hence the degree of CMI in the host response to infection.     

白细胞介素4和白细胞介素10基因多态性与胃癌易感性的关系

目的：分析白细胞介素4(IL-4)rs2070874,白细胞介素10(IL-10)rs1800871、rs1800872基因型及其基因频率在汉族成年胃癌患者与正常对照人群中的分布情况,探讨 IL-4,IL-10基因多态性与胃癌临床易感性的关系。方法病例组胃癌患者84例,正常对照组105例,两组均留取外周静脉血提取 DNA,利用直接测序法对 IL-4 rs2070874,IL-10 rs1800871、rs1800872进行基因型测定,分析各位点多态性与胃癌临床易感性关系。结果 IL-4 rs2070874基因多态性在病例组与对照组等位基因之间、基因型之间的分布差异有统计学意义(P <0.05);IL-10 rs1800871、rs1800872基因多态性在病例组与对照组等位基因之间、基因型之间的分布差异无统计学意义(P >0.05)。结论 IL-4 rs2070874基因多态性与胃癌感染易感性有关,而 IL-10 rs1800871、rs1800872位点基因多态性与胃癌易感性可能不相关。     

烧伤患者血浆白介素-8和白介素-10水平的变化

目的：观察严重烧伤患者血浆白介素 ８（ＩＬ ８）和ＩＬ １０ 水平的变化,探讨其与烧伤后全身感染的关系。方法：收集１９ 例严重烧伤患者的血浆,利用酶联免疫吸附（ＥＬＩＳＡ）法测定血浆中ＩＬ ８ 和ＩＬ １０ 水平。结果：烧伤后患者血浆ＩＬ ８ 和ＩＬ １０ 水平急剧升高;非脓毒症患者血浆ＩＬ ８ 和ＩＬ １０ 水平在伤后逐渐降至正常,而脓毒症组患者则急剧升高。３ 例死于脓毒症者血浆ＩＬ ８ 和ＩＬ １０ 持续在高水平状态。结论：烧伤能诱导机体产生ＩＬ ８ 和ＩＬ １０;过高的ＩＬ １０ 可能与烧伤后感染有关     

Plasma and lymph pharmacokinetics of recombinant human interleukin-2 and polyethylene glycol-modified interleukin-2 in pigs

Modification of recombinant human interleukin-2 (IL-2) with polyethylene glycol (PEG-IL-2) decreases clearance and might favor absorption into the lymphatics, due to its increased molecular weight. In the present study, we compared the plasma and lymph concentrations of IL-2 and PEG-IL-2 in Yorkshire pigs. The IL-2 regimens were i.v. bolus (0.1-1.6 x 10(6) I.U., MIU/kg), 15-min i.v. infusion (0.1 MIU/kg), or s.c. bolus (0.1-3.0 MIU/kg). The PEG-IL-2 doses were 15-min i.v. infusion (0.01 MIU/kg) or s.c. bolus (0.01-0. 10 MIU/kg). Lymph and plasma data were analyzed using noncompartmental methods and NONMEM. Bioavailability of IL-2 was route- and dose-dependent. Bioavailability of i.v. bolus doses of >/=0.16 MIU/kg was complete but only 39% at 0.1 MIU/kg. For the infusion and s.c. doses, bioavailability was 28 and 42%, respectively. Noncompartmental and NONMEM estimates of clearance and volume of distribution at steady state agreed: 300 ml/h/kg and 570 ml/kg, respectively, for IL-2. The ratio of the area under the curve in lymph and plasma increased from 0.67 to 3.4 when comparing i.v. and s.c. routes, and the s.c. delivery advantage (ratio of dose-normalized ratio of the area under the curve in lymph after s.c. and i.v. administration) was 6.6 to 16. For PEG-IL-2, bioavailability was 100%, clearance was 5.9 ml/h/kg, and volume of distribution at steady state was 370 ml/kg. The ratio of the area under the curve in lymph and plasma increased from 0.33 (i.v.) to 1. 2 (s.c.), and the s.c. delivery advantage was 3.8. Subcutaneous dosing would be favored over i.v. dosing, and IL-2 would be favored over PEG-IL-2 to maximize lymph and minimize plasma exposure. Because IL-2 efficacy may be related to lymph concentrations, dosing regimens can now be designed to test this hypothesis.     

类风湿性关节炎辨证分型与白细胞介素6、18血清水平的关系

目的:探讨白细胞介素6(IL-6)和白细胞介素18(IL-18)血清水平与类风湿性关节炎(RA)中医辨证分型的关系。方法:采用酶联免疫吸附试验(ELISA)双抗体夹心法检测RA患者和健康人的外周血IL-6和IL-18的血清水平,分析不同证型两指标之间及其与C反应蛋白、类风湿因子含量的相关性。结果:RA患者IL-6和IL-18血清水平与健康人比较差异具有显著性,活动期RA患者IL-6水平显著高于稳定期患者(P<0.05)。风寒湿阻型患者血清IL-6浓度明显高于痰瘀互结型与肝肾两虚型(P<0.05),而与风湿热郁型无明显差异(P>0.05);而风寒湿阻型患者血清IL-18浓度明显高于风湿热郁型与肝肾两虚型(P<0.05),而与痰瘀互结型无明显差异(P>0.05)。结论:IL-6血清水平与RA的活动性密切相关,且与其中医辨证分型存在一定的联系。     

Pro-inflammatory cytokines and the pathogenesis of Gaucher's disease: increased release of interleukin-6 and interleukin-10

Gaucher's disease is characterized by hepatosplenomegaly, bone-marrow infiltration, osteonecrosis and bone thinning, associated with the presence of pathological macrophages that contain undegraded glycosphingolipids. To investigate the possible role of cytokines in the systemic and local manifestations of established Gaucher's disease, interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF alpha) and interleukin-10 (IL-10) were measured in freshly-separated serum. Samples from eight male and 14 female patients with type 1 Gaucher's disease were compared with sera from 22 healthy age- and sex-matched controls. Concentrations of IL-6 and IL-10 were significantly elevated in sera from patients with Gaucher's disease (11.9 +/- 1.8 (SEM) pg/ml and 5.4 +/- 0.5 (SEM) pg/ml, respectively) compared with those of controls (4.1 +/- 0.9 (SEM) and 0.8 +/- 0.3 (SEM) pg/ml, p < 0.0001). No significant differences in concentrations of TNF alpha or IL-1 beta were identified. IL-6 has been implicated in the development of localized osteolysis in multiple myeloma and in the development of post-menopausal osteoporosis. High concentrations of IL- 6 in the serum of patients with Gaucher's disease may thus reflect the development of the bone lesions commonly associated with this disorder. Since IL-6 and IL-10 are important regulators of lymphocyte growth and differentiation, and IL-6 concentrations were significantly raised in patients with oligo- or polyclonal increases in serum immunoglobulins, enhanced release of these cytokines from pathological macrophages provides a pathological link between Gaucher's disease and associated lympho-proliferative disorders.      

强直性脊柱炎患者血清介素1β、2、6及肿瘤坏死因子-α测定的意义

目的观察强直性脊柱炎（AS）患者外周血清白介素-1β（IL-1β）、白介素-2（IL-2）、白介素-6(IL-6)、肿瘤坏死因子-α（TNF-α）、红细胞沉降率（ESR）、C反应蛋白（CRP）、免疫球蛋白（IgA、IgG、IgM）水平，并分析它们与强直性脊柱炎疾病活动指数（BASDAI）相关性。 方法测定45例AS患者及30例健康体检者的IL-1β、2、6及TNF-α，CRP、IgA、IgG、IgM、ESR水平。以Bath强直性脊柱炎疾病活动指数（BASDAI）评定AS患者疾病活动性，取BASDAI中位数将患者分为活动组及非活动组，比较AS患者与对照组，活动组与非活动组各实验指标，分析它们与BASDAI的相关性。 结果AS患者ESR、CRP、IgA、IgM、IgG、IL-1β、IL-2、IL-6及TNF-α水平与对照组之间差异有统计学意义（P<0.05）。AS患者活动组CRP、IL-2与IL-6较非活动组差异有统计学意义（P<0.05）。AS患者CRP与IL-6，IL-2与IL-6，IgA与IgG两两之间成正相关，但只有IL-2、IL-6及CRP与BASDAI之间成正相关。 结论IL-2、IL-6与CRP可作为AS疾病活动性的参考指标。     

Colony promoting activity: differences from interleukin-3 and similarities to interleukin-6

The supernatant of long-term bone marrow culture contains colony promoting activity (CPA) which does not have granulocyte-macrophage colony stimulating activity (CSF) but which enhances granulocyte-macrophage (GM) colony formation in the presence of CSF. CPA might consist of IL-3 or IL-3-like activity, since CPA stimulates proliferation and differentiation of more immature cells to CSF-responding granulocytes-macrophage progenitors (GM-CFC), and since IL-3 also stimulates immature hemopoietic cells to proliferate and differentiate to functional blood cells. IL-1 and IL-6 are also known to enhance GM colony formation. One or both of these molecules can accordingly be another candidate for CPA. In the present study, GM-CSF activity of IL-3 was dependent on the batch of serum: it was negative in the presence of fetal calf serum, but positive in the presence of horse serum. In contrast, GM-CSF and CPA showed no such dependence on the batch of serum. The addition of IL-3 to GM colony assay system did not enhance but rather suppressed GM colony formation. The supernatant of long-term bone marrow culture which contains substantial levels of CPA did not stimulate proliferation of IL-3 dependent DA-1 cells, but facilitated the proliferation of IL-6 dependent, MH60.BSF2 cells. No detectable level of IL-1 activity was found in the supernatant. These results indicate that CPA is different from IL-1, IL-3 or GM-CSF, but similar to or the same as IL-6.     

氯诺昔康超前镇痛对术后疼痛及病人血清白介素-2和白介素-6水平的影响

目的研究以氯诺昔康行超前镇痛对术后疼痛及病人围术期血清白细胞介素．2（IL-2）和自细胞介素-6（IL-6）水平的影响。方法60例ASAⅠ～Ⅱ级的子宫肌瘤患者，硬膜外麻醉下行经腹子宫全切术，随机分为三组：A组，不施行超前镇痛；B组，术前30min缓慢静注氯诺昔康16mg；C组，术毕时缓慢静注氯诺昔康16mg。三组术后均不行自控镇痛（PCIA），如果术后静息时患者主诉疼痛难忍，肌注曲马多镇痛（100ms／次）。分别于术前、术毕时、术后12h和术后24h抽取外周静脉血，采用放射免疫分析法测定患者血清中IL-2和IL-6的浓度，并于术后不同时间点观察视觉模拟评分（VAS）、术后应用镇痛药的比例和不良反应的发生率。结果B组的VAS评分在术后各时间点均显著低于A组，C组在术后4hVAS疼痛评分显著低于A组（P〈0．01）。A组术后24h内用镇痛药的患者占30％，显著高于B、C组（P〈0．05）。B组IL-2和IL-6的浓度波动均不明显；在A组和C组，术后IL-2的浓度显著降低而IL-6的浓度显著升高，与B组的差异具有显著性；C组IL-2和IL-6的浓度与A组比较差异无显著性。结论以氯诺昔康行超前镇痛能够减轻下腹部手术的术后疼痛，减少术后镇痛药的应用，能有效的抑制应激反应，减轻术后免疫抑制。