IL-12及IL-10在桥本甲状腺炎发病机制中作用的研究进展

桥本甲状腺炎是一种常见的慢性自身免疫性疾病,表现为辅助性T细胞(Th)1占优势。 Th1类细胞因子白细胞介素(IL)-12表达增加,在该病的诱发及慢性迁延中起重要作用,Th2类细胞因子IL-10表达的下调也与该病有关,且随病情变化二者表达水平有所不同。因此,这些细胞因子可作为病情变化的监测指标,并且可通过调节细胞因子的表达水平从而使失衡的Th1／Th2细胞趋于平衡。这可能为桥本甲状腺炎的治疗开拓一条新途径。     

支气管哮喘患者IL-12/IL-13失衡的研究

目的　了解支气管哮喘患者外周血白细胞介素 12 (IL- 12 )、白细胞介素 13(IL- 13)是否失衡。方法　选取急性发作期哮喘患者 (哮喘组 2 5例 ) ,健康志愿者 (对照组 ) 15例。分别对哮喘组、对照组留取血标本 ,采取双抗体夹心酶联免疫吸附法 (EL ISA)检测上述两组血清中 IL - 12、IL - 13水平 ,并对测定结果进行统计学处理。结果　哮喘组 IL - 12水平为 (5 8.5 0± 14 .2 5 ) mg/ L ,较对照组 (85 .5 2± 13.14 ) ng/ L明显降低 ,差异有显著性 (P<0 .0 1) ;哮喘组 IL- 13水平为 (131.2 7± 2 8.4 5 ) ng/ L较对照组 (92 .30± 14 .4 3) ng/ L 明显增高 ,差异有显著性 (P<0 .0 1)。结论　哮喘患者体内 IL- 13过度产生 ,IL- 12则产生不足 ,使 IL- 12 / IL- 13失衡。     

Ribavirin up-regulates IL-12 p40 gene expression and restores IL-12 levels in Leishmania-treated PBMCs

Ribavirin, a nucleoside analogue that interferes with viral mRNA synthesis and inhibits the replication of RNA and DNA viruses, has been recently proposed as an effective immune response modulator. In the present report, we studied the effect of ribavirin on IL-12 p40 gene expression in peripheral blood mononuclear cells (PBMCs) of healthy subjects. We also studied ribavirin effects on PBMCs activated with lipopolysaccharide (LPS) and phytohaemagglutinin (PHA) and treated with Leishmania donovani antigens. We provide evidence that ribavirin was able to up-regulate IL-12 p40 gene expression and to restore levels of IL-12 p40 gene expression and IL-12 secretion in fully activated PBMCs that were strongly inhibited by L. donovani antigens. Because effective management of leishmanial disease is usually associated with a prevalent T-helper 1 immune response with elevated production of IL-12,our preliminary results may be of particular interest, provided that they will be confirmed by further in vitro and in vivo studies, when considering a possible use of ribavirin as adjuvant in severe leishmanial disease.     

Regulation of ITAM-positive receptors: role of IL-12 and IL-18

Our previous studies have identified mechanisms by which cytokine production, blocked by Ly49G2 receptor cross-linking, can be overridden. In this study we analyzed the regulation of other ITAM-positive receptor signaling on NK, NKT, and T cells and characterized the biochemical pathways involved in this signaling. Our studies demonstrate that cross-linking of NKG2D and NK1.1 results in a synergistic NK IFN-gamma response when combined with IL-12 or IL-18. Examination of NKT- and T-cell responses demonstrated that cross-linking of NKG2D and CD3 resulted in potent synergy when combined with IL-12 and, to a lesser degree, with IL-18. We have now found that both the p38 MAP kinase and the ERK-dependent signal transduction pathways are required for the synergistic response. Further mechanistic examination of the synergy indicated a potent up-regulation of total IFN-gamma mRNA in the nuclear and the cytoplasmic compartment, but mRNA half-life was not affected. Fifteen minutes of IL-12 pretreatment was sufficient to result in maximal synergistic activation, indicating that the response of the cells to the IL-12 signal was rapid and immediate. Thus, our data demonstrate that multiple convergent signals maximize the innate immune response by triggering complementary biochemical signaling pathways.     

Serum IL-6 and IL-12 levels in breast cancer patients

Previous studies indicated that interleukins 6 & 12 are multifunctional cytokines which regulate of immune response and cancer cell proliferation. We measured serum levels of these cytokines in 40 females with breast cancer and examined their correlation with clinicopathological variables including stages of the disease and estrogen and progesterone receptor expression on tumor cells. Serum levels of IL-6 (mean =111.38 pg/ml) as well as IL-12 (mean=1142.75 pg/ml) were significantly increased in breast cancer patients as compared to controls (mean 1.75 pg/ml &19.90 pg/ml respectively). A statistically significant correlation was found between levels of IL-6 as well as IL-12 and progression of the tumor (P < 0.05). However, no statistical difference was found in serum levels of these cytokines between metastatic and non-metastatic cases. Both cytokines negatively correlated with estrogen and progesterone receptor expression on tumor cells. In conclusion, serum levels of IL-6 and IL-12 are highly elevated in breast cancer patients and correlate with tumor progression. Assays for serum levels of IL-6 and IL-12 can be used as predictive non-invasive tests for tumor progression in breast cancer patients.     

Partial impairment of interleukin-12 (IL-12) and IL-18 signaling in Tyk2-deficient mice

Tyk2 is activated in response to interleukin-12 (IL-12) and is essential for IL-12-induced T-cell function, including interferon-gamma (IFN-gamma) production and Th1 cell differentiation. Because IL-12 is a stimulatory factor for natural killer (NK) cell-mediated cytotoxicity, we examined whether tyk2 is required for IL-12-induced NK cell activity. IL-12-induced NK cell activity in cells from tyk2-deficient mice was drastically reduced compared to that in cells from wild-type mice. IL-18 shares its biologic functions with IL-12. However, the molecular mechanism of IL-18 signaling, which activates an IL-1 receptor-associated kinase and nuclear translocation of nuclear factor-kappaB, is different from that of IL-12. We next examined whether biologic functions induced by IL-18 are affected by the absence of tyk2. NK cell activity and IFN-gamma production induced by IL-18 were reduced by the absence of tyk2. Moreover, the synergistic effect of IL-12 and IL-18 for the production of IFN-gamma was also abrogated by the absence of tyk2. This was partially due to the absence of any up-regulation of the IL-18 receptor treated with IL-12, and it might suggest the presence of the cross-talk between Jak-Stat and mitogen-activated protein kinase pathways in cytokine signaling.     

Whole Tumor Cell Vaccine Adjuvants: Comparing IL-12 to IL-2 and IL-15

Cancer immunotherapy (passive or active) involves treatments which promote the ability of the immune system to fight tumor cells. Several types of immunotherapeutic agents, such as monoclonal antibodies, immune checkpoint inhibitors, non-specific immunomodulatory agents, and cancer vaccines are currently under intensive investigation in preclinical and clinical trials. Cancer vaccines induce permanent activation of the immune system and may be considered the most promising method for cancer treatment, especially in combination with other agents of passive immunotherapy. Among various approaches to cancer vaccines, whole tumor cell vaccines have been attracting attention for several years. Despite their low to moderate clinical effects, these vaccines have numerous advantages. Their ability to generate immune responses against tumor-associated antigens reduces the possibility for tumor cells to escape and facilitates the development of “off-the-shelf” allogeneic tumor vaccines. Understanding the reciprocal interactions between tumor cells and leukocytes is a key to harness the full potential of whole cell vaccination. Cytokines are considered as potent immunomodulatory molecules which behave as adjuvants in whole tumor cell vaccines. Improved mechanistic understanding of key cytokines in tumor immunity will serve as a resource for rational design of whole cell cancer vaccines. Although there are several reports about the use of different immunostimulatory cytokines as adjuvants, interleukin (IL)-12 appears to have superior effects compared to other cytokines. This review describes the effects of IL-12 compared to other immunomodulatory cytokines, such as IL-2 and IL-15, and highlights its application in whole cell tumor vaccination.     

急性冠状动脉综合征患者血清IL-10及IL-12水平测定

目的 :探讨白细胞介素 - 10 (IL- 10 )、白细胞介素 - 12 (IL- 12 )对动脉粥样硬化 (AS)形成和发展的影响。方法 :分别对 18例急性心肌梗死 (AMI)患者于发病当天及第 3,5 ,7,10 ,14天 ;14例不稳定型心绞痛 (UAP)患者及 10例健康对照者测定血清 IL - 10、IL - 12水平。结果 :1U AP患者 IL - 10、IL - 12水平显著高于对照组。 2A MI患者血清 IL - 10于发病当天至第 5天显著高于其他两组 ,并于第 3天达高峰。 IL - 12于发作当天及第 10～ 14天显著高于对照组。3AMI死亡组 IL - 10水平明显高于生存组 ,而 IL - 12无显著性差异。结论 :提示急性冠状动脉事件患者 IL - 10、IL - 12升高 ,二者可能参与了 A S的形成和发展 ,并可作为急性期预测指标。     

Rafting with the IL-12 receptor

In this issue of Blood, Kondadasula and colleagues provide important clues for understanding successful cancer immunotherapy by demonstrating an intriguing mechanism through which CD16 synergizes with IL-12 to induce interferon-gamma (IFN-gamma) production by NK cells.     

白细胞介素-12及白细胞介素-18致小鼠脾虚的研究

目的：观察白细胞介素-12(IL-12)及白细胞介素-18(IL-18)能否导致脾虚，研究脾虚与IL-12及IL-18的关系。方法：60只小鼠随机分为脾虚组、IL组和对照组。采用利血平制作脾虚动物模型组，IL组每日腹腔注射IL-12、IL-18。采用免疫分析技术检测3组小鼠血浆IL-12、IL-18的含量。结果：IL-12及IL-18引起明显脾虚证的表现，与利血平制作脾虚动物模型组相似。脾虚组和IL组血浆IL-12、IL-18的含量明显升高。结论：IL-12、IL-18可导致脾虚，血浆IL-12、IL-18的含量可作为脾虚证的实验室参考指标。     

白细胞介素10基因转染对小鼠心脏移植排斥反应中细胞因子表达的影响

目的 :探讨白细胞介素 10 (IL 10 )基因转染对小鼠心脏移植排斥反应中IL 12、IL 15、IL 18和IL 4表达的影响。方法 :采用小鼠颈部心脏移植模型 ,随机分为 3组 :对照组、移植组和IL 10组。于术后第 5天取移植心脏 ,用逆转录聚合酶链式反应 (RT PCR)法观察IL 12、IL 15、IL 18、IL 4及IL 10的表达情况。结果 :移植组IL 12、IL 15、IL 18表达与对照组比较明显升高 ,IL 10、IL 4表达显著降低 (均P <0 .0 1)。IL 10组IL 12、IL 15、IL 18表达与移植组比较明显降低 ,而IL 4及IL 10表达显著升高 (均P <0 .0 1)。结论 :IL 10基因转染抑制心脏移植排斥反应主要与其抑制IL 12、IL 15、IL 18等Th1型细胞因子的表达 ,促进Th2型细胞因子IL 4的表达 ,使免疫反应由Th1型向Th2型偏移有关     

LADA患者血清IL-12、IL-18及血淋巴细胞亚群研究

与2型糖尿病组及正常对照组相比,成人隐匿性自身免疫糖尿病(LADA)组外周血淋巴细胞亚群有明显变化,白细胞介素12(IL12)、白细胞介素18(IL18)水平亦升高。LADA存在明显细胞免疫紊乱,并与胰岛功能密切相关。     

血清IL-5、IL-12水平在不同海拔COPD发病中的探讨

目的观察血清IL-5、IL-12相关Th1/Th2失衡在不同海拔地区COPD发病中的作用。方法选取COPD患者和健康体检人群各32例作为中度海拔组,玉树州人民医院COPD患者和健康体检人群各32例作为高海拔组,所有患者均依据2007年GOLD标准诊断,分别在急性期和缓解期空腹采静脉血标本3 ml,用ELISA测定IL-5、、IL-12水平。结果中海拔COPD患者血清IL-5水平:急性期组、缓解期组及健康组两两比较有差异均有显著性,P<0.05;血清IL-12水平:急性期组和缓解期组、缓解期组和健康组比较差异均有显著性,P<0.05。中、高海拔COPD患者缓解期血清IL-5水平:中海拔缓解期组和健康组,中、高海拔缓解期组、中、高海拔健康组比较差异均有显著性,P<0.05;血清IL-12水平:中海拔缓解期组和健康组,中、高海拔缓解期组、高海拔缓解期组和健康组比较差异均有显著性,P<0.05。结论 IL-5、IL-12相关Th1/Th2失衡可能参与了COPD的发病并与海拔有一定的关系。