Reduced Expression of IL-1β and IL-18 Proinflammatory Interleukins Increases the Risk of Developing Cervical Cancer

Background: The objective of this study was to analyze the gene expression profile of the proinflammatoryinterleukins, (IL-1β and IL-18) in patients with premalignant lesions and cervical cancer. Methods: Total IL-1β andIL-18 mRNA was quantified by qPCR to obtain the expression data in cervical tissues. A total of 74 cervical biopsieswere obtained from women undergoing a colposcopy. The samples were divided into: normal (19), low level lesions(LSIL) or NIC I (17), high level lesions (HSIL) or CIN II and CIN III (29) and cancer (9). The normal cervical tissuesamples were included as controls. The OR and 95% CI were calculated for the determination of the risk of progressionbetween each type of lesion and cancer using logistic regression. Results: The results showed that an increase in therisk of progression of pre-neoplastic lesions to cancer was between 2.5 and 2.08 times higher in women with lowerIL-1β and IL-18 expression, respectively. Conclusions: This study provided evidence that IL-1β and IL-18 are potentialbiomarkers that can be explored in further studies for monitoring the evolution of pre-neoplastic lesions and avoidingovertreatment or undertreatment of the patients.     

CRP, TNFα, IL-1ra, IL-6, IL-8 and IL-10 in blood serum of colorectal cancer patients

Blood serum cytokines: TNFalpha, IL-1ra, IL-6, IL-8, IL-10 as well as CRP were investigated in patients with colorectal cancer, prior treatment and 1, 10 and 42 days after surgery. There was an increase of the levels of CRP, IL-6 and IL-10 in most patients 24 hours after surgery. The levels of IL-1ra were elevated in patients in stage C and in several patients in stage B of the disease and there was a decrease of circulating TNFalpha in stage B patients. On day 10 and 42 after surgery, the levels of cytokines followed various patterns.     

Serum levels of IL-6 and IL-1β can predict the efficacy of gemcitabine in patients with advanced pancreatic cancer

Background:

With this study, we sought to characterise the impact of pro-inflammatory cytokines on the outcomes of gemcitabine monotherapy (GEM) in patients with pancreatic cancer (PC).

Methods:

Treatment-naive patients with advanced PC and no obvious infections were eligible for enrolment. All of the patients were scheduled to undergo systemic chemotherapy. Serum pro-inflammatory cytokines were measured using an electro-chemiluminescence assay method before chemotherapy. High cytokine levels were defined as values greater than the median. Clinical data were collected prospectively.

Results:

Sixty patients who received GEM were included in the analysis. High IL-6 and IL-1β levels were poor prognostic factors for overall survival in a multivariate analysis (P=0.011 and P=0.048, respectively). Patients with both a high IL-6 level and a high IL-1β level exhibited shortened overall and progression-free survival, a reduction in the tumour control rate, and a high dose intensity of GEM compared with patients with low levels of both IL-6 and IL-1β.

Conclusion:

The serum levels of IL-6 and IL-1β predict the efficacy of GEM in patients with advanced PC.     

Down-regulation of IL-6, IL-8, TNF-α and IL-1β by glucosamine in HaCaT cells, but not in the presence of TNF-α

There is considerable evidence that glucosamine exerts an inhibitory effect on inflammatory cytokine expression in cells. Glucosamine has been recommended as a promising anti-inflammatory modulator, which has been applied in clinical trials for attenuation of the inflammatory process. However, it is unknown whether glucosamine reduces the expression of TNF-α-induced inflammatory cytokines in HaCaT cells. The anti-inflammatory effects of curcumin in HaCaT cells have been extensively investigated in several studies. Thus, in this study we investigated the expression of IL-6, IL-8, TNF-α and IL-1β in glucosamine-treated HaCaT cells, and the effects of glucosamine were compared to those of curcumin-treated HaCaT cells. Our data showed that the expression of IL-6, IL-8, TNF-α and IL-1β was decreased by glucosamine treatment in the HaCaT cells. In contrast, the expression of IL-6, IL-8, TNF-α and IL-1β was not attenuated by glucosamine treatment in the TNF-α-treated HaCaT cells. Notably, curcumin induced an increased expression of IL-8 and IL-1β in the HaCaT cells, but not that of IL-6 and TNF-α. On the other hand, curcumin attenuated the expression of IL-6 and IL-8 in the TNF-α-treated HaCaT cells. Our data indicated that glucosamine induced the down-regulation of IL-6, IL-8, TNF-α and IL-1β expression in the HaCaT cells. However, the stimulation of TNF-α abolished the inhibitory effects of glucosamine on the expression of inflammatory cytokines in the HaCaT cells. Thus, even though glucosamine induces the down-regulation of inflammatory cytokines in HaCaT cells, the anti-inflammatory role of glucosamine in TNF-α-mediated inflammatory skin diseases should be investigated.     

Combined treatment of IL-1α and TNF-α potentiates the antitumour effect of hyperthermia

Vasoactive cytokines, such as IL-1α and TNF-α, modulate the homeostatic state at the endothelial surface and cause various types of pathological damage in vascular systems. We investigated the potential therapeutic effects of IL-1α and TNF-α in combination with hyperthermia on SCK tumours grown in the legs of A/J mice. We first determined the effect of cytokines on tumour blood perfusion with the ⁸⁶Rb uptake method. When the host mice were given an i.p. injection of 25 μg/kg IL-1α or 50 μg/kg TNF-α, the tumour blood perfusion markedly declined to 46 and 82% of control, respectively. The combination of IL-1α and TNF-α reduced the ⁸⁶Rb uptake to 41% of control. Hyperthermia at 42·5°C for 1 h reduced the tumour blood flow to 71% of control. The tumour blood perfusion decreased further to 20% of control when the tumours were heated for 1 h at 42.5°C starting 4h after the injection of both IL-1α and TNF-α. The changes in clonogenic cell numbers in SCK tumours, as determined by the in vivo-in vitro assay, following various treatments was also investigated. At 4h after an i.p. injection of 25 μg/kg IL-1α or 50 μg/kg TNF-α, the clonogenicity of SCK tumours significantly decreased to 29 or 37% of control, respectively. Heating at 42.5°C for 1h caused a decline in the clonogenic cell number to 30% of control. When both IL-1α and TNF-α were given and tumours were heated 4h later at 42·5°C for 1h, the clonogenic cell number markedly declined to 0.4% of control. The time needed for control tumours to reach 4x their initial volume was about 3 days, and treatment with IL-1α or hyperthermia alone induced a tumour delay growth by about 1 day. The combined injection of IL-1α and TNF-α followed by a heating at 42·5°C for 1h delayed the tumour growth by 6 days. The results in this study suggest that prior impairment of blood circulation by the combined treatment of IL-1α and TNF-α potentiates hyperthermic damage in tumours.     

IL-6、IL-8与卵巢癌

与卵巢癌有关的细胞因子众多，其中IL-6和IL-8的异常表达在卵巢癌的发生、发展中起着十分重要的作用。对其深入探究将有助于阐明卵巢癌的发病机制，协助临床诊断和病情估计，并为卵巢癌的生物治疗提供新的线索和途径。     

IL-6、IL-8与卵巢癌

与卵巢癌有关的细胞因子众多,其中IL-6和IL-8的异常表达在卵巢癌的发生、发展中起着十分重要的作用.对其深入探究将有助于阐明卵巢癌的发病机制,协助临床诊断和病情估计,并为卵巢癌的生物治疗提供新的线索和途径.     

IL-35、IL-39、IL-27在肿瘤微环境中的调节作用

白细胞介素(IL)家族能直接或间接地刺激肿瘤细胞增殖、存活和扩散,并进一步塑造肿瘤微环境,从而在一定程度上影响肿瘤的生长与转化。研究发现IL-12家族的新成员IL-35、IL-39、IL-27在多种肿瘤中发挥相关的特异性免疫功能,可能是肿瘤研究的重要靶向分子。     

IL-1 stimulates growth and metastasis of human cancer xenografts in nude mice

Interleukin 1 (IL-1) is a pluripotent cytokine that promotes inflammation, angiogenesis, tumor growth andmetastasis in experimental models; its presence in some human cancers is associated with tumor progression. Alex-ander et al. recently reported that inhibition of IL-1 by its receptor antagonist (IL-1Ra) retarded growth of IL-1-ex-pressing human cancer xenografts in nude mice (Clin Cancer Res 2006, 12:1088 ~1096). IL-1 mRNA and pro-tein levels were determined in clinical tumor samples…     

IL-8 is a mediator of NF-κB induced invasion by gliomas

Glioblastoma (GBM) is the most common and deadly form of primary brain tumor with a median survival of eleven months, despite use of extensive chemotherapy, radiotherapy and surgery. We have previously shown that nuclear factor-kappa B (NF-κB) is aberrantly expressed in GBM tumors and primary cell lines derived from tumor tissue. Here we show that IL-8, a chemokine is also aberrantly expressed by GBM cell lines and expression of IL-8 is in large part, attributable to the aberrant activation of NF-κB. We hypothesized that invasiveness of GBM cells is driven at least in part by aberrantly expressed IL-8. In support of the hypothesis we found that treatment of glioma cells with an IL-8 neutralizing antibody markedly decreased their invasiveness compared to cells treated with control IgG or left untreated. Furthermore, downregulation of IL-8 protein production with use of IL-8 targeted siRNA also resulted in decreased invasion in matrigel. We next investigated the presence of IL-8 receptors by FACS analysis and found that GBM cells (U87, U251, D54 and LN229) only express CXCR1 but not CXCR2. Treatment of U87 cells with a blocking CXCR1 antibody reduced their invasion through matrigel. Finally, we found that addition of exogenous IL-8, following downregulation of NF-κB which results in loss of endogenous IL-8 production, incompletely restored tumor cell invasion. Our data indicate that IL-8 is necessary but not solely responsible for glioma cell invasion and mediates its effect in an autocrine manner.     

IL-7 + IL-15 are superior to IL-2 for the ex vivo expansion of 4T1 mammary carcinoma-specific T cells with greater efficacy against tumors in vivo

Regression of established tumors can be induced by adoptive immunotherapy (AIT) with tumor draining lymph node (DLN) lymphocytes activated with bryostatin and ionomycin (B/I). Tumor antigen-sensitized DLN lymphocytes from BALB/c mice with 10-day 4T1 mammary carcinomas were harvested, activated with B/I, and expanded in culture with either interleukin-2 (IL-2) or IL-7 + IL-15. Cell yields, proliferation, phenotypes, and in vitro responses to tumor antigen were compared for cells grown in different cytokines. These T cells were also tested for antitumor activity against established 4T1 mammary carcinomas after inoculation of tumor cells subcutaneously (s.c.). IL-7/15 resulted in much faster and more prolonged proliferation of B/I-activated T cells than culturing the same cells in IL-2. This resulted in approximately 5–10-fold greater yields of viable cells. Culture in IL-7/15 yielded higher proportions of CD8⁺ T cells and a higher proportion of cells with a central memory phenotype. T cells grown in IL-2 had higher interferon-gamma (IFN-γ) release responses to tumor antigen than cells grown in IL-7/15. Adoptive transfer of B/I-activated T cells grown in IL-7/15 demonstrated much greater efficacy against 4T1 tumors in vivo. Activation of tumor antigen-sensitized T cells with B/I and culture in IL-7 + IL-15 is a promising modification of standard regimens for production of T cells for use in AIT of cancer.     

IL-4通过抑制树突状细胞合成IL-10以促进IL-12的分泌

长久以来,IL-4被认为是强效诱导Th2分化的细胞因子,近来越来越多的文献报道IL-4也能促进树突状细胞(dendriticcella,DCa)合成IL-12,进而诱导Th1型免疫应答,但是其中的具体机制有待进一步阐明. 作者首先研究了IL-4对LPS诱导DCa成熟分泌细胞因子的影响.结果发现IL-4抑制LPS诱导的DCa分泌IL-10,同时促进IL-12 p70的产生.并且,IL-4是通过下调IL-10 mRNA或上调IL-12p35 mRNA转录进而影响相应蛋白的生成.同样条件下IL-4并不影响LPS活化的DCs分泌IL-6和TNF-α.此外,IL-4只能抑制DCa合成IL-10,并不抑制反而促进LPS诱导的B细胞分泌IL-10.因此IL-4对IL-10的抑制作用具有细胞特异性,也证实IL-4可通过促进B细胞分泌IL-10诱导Th2型免疫应答.     

胃癌患者IL-10,IL-12的检测及其临床意义

目的检测胃癌患者IL-10、IL-12在癌组织和癌周组织中的含量及术前和术后1周、2周血清中浓度的变化并探讨其意义。方法用ELISA法检测了22例胃癌患者IL-10、IL-12在癌组织和癌周组织中的含量及术前和术后1周、2周血清中的浓度,以16例健康人为对照。结果胃癌患者IL-10含量在癌组织中高于癌周组织,其中IL-10含量在Ⅲ、Ⅳ期癌组织和癌周组织中均高于Ⅰ、Ⅱ期癌组织和癌周组织,IL-12含量则相反。胃癌患者血清中IL-10浓度升高,且血清IL-10浓度Ⅲ、Ⅳ期较Ⅰ、Ⅱ期高,术后1周、2周血清中IL-10浓度逐渐下降,但仍高于对照组浓度,IL-12浓度则相反。结论胃癌细胞可能分泌IL-1 0抑制IL-1 2,使机体的免疫力降低。IL-10,IL-12的检测可反映胃癌病期、判断疗效和估计预后。     

IL-8与肿瘤

IL-8是α型趋化因子,对多种白细胞有趋化、激活作用,在炎症、免疫反应、动脉硬化及DIC中发挥一定的病理作用.同时它也是促血管生成因子,与肿瘤血管新生、生长以及肿瘤的侵袭转移有密切关系,影响疾病的预后.现对IL-8的分子生物学特性、与肿瘤生长的关系和作用机制以及在肿瘤治疗中的研究意义作简要概述.     

IL-18的研究进展

白细胞介素18(interleukin-18,IL-18)首先作为INF-γ诱导因子,由于其在炎症和免疫应答中的重要作用而被发现[1]。IL-18是1995年Okamura等在脂多糖诱导的小鼠中毒性休克的肝脏中提取出[1],结构及胞内信号转导通路类似于IL-1家族,而功能类似于IL-12家族的1种蛋白分子。但是与IL-12相比,IL-18有更强的诱导生成INF-γ的能力。     

IL-8与肿瘤

IL-8是α型趋化因子，对多种白细胞有趋化、激活作用，在炎症、免疫反应、动脉硬化及DIC中发挥一定的病理作用。同时它也是促血管生成因子，与肿瘤血管新生、生长以及肿瘤的侵袭转移有密切关系，影响疾病的预后。现对IL-8的分子生物学特性、与肿瘤生长的关系和作用机制以及在肿瘤治疗中的研究意义作简要概述。