interleukin-8 and Uterine-Cervical-Neoplasms

IMeasurement of tumor markers level in human body fluids, mainly in serum may be useful for diagnosis, therapy monitoring and early recurrence detection. SCC-Ag, Cyfra 21-1, CEA, CA 125 and TPS are of a clinical value in uterine cervical cancer despite their diverse significance. Other biological markers that could be measured in serum as well as in tumor tissue are cytokines: VEGF, IL-6, IL-8, IL-4, IL-10, leptin, stromal drive factor (SDF- 1), although assessment of their importance needs further examination. Elevation of uterine cervical cancer hypoxia markers such as HIF 1a, CA 9, GLUT-1 is combined with poorer clinical outcome prognosis.

Topics: Antigens, Neoplasm; Biomarkers, Tumor; Blood Chemical Analysis; CA-125 Antigen; Carcinoembryonic Antigen; Female; Humans; Interleukin-10; Interleukin-4; Interleukin-6; Interleukin-8; Keratin-19; Keratins; Neoplasm Staging; Prognosis; Serpins; Uterine Cervical Neoplasms; Vascular Endothelial Growth Factor A

Chronic inflammation has been proven to be an important factor in carcinogenesis. Cytokines are the central mediators in the inflammatory microenvironment, and their release may be influenced by soluble HLA-G (sHLA-G). The aim of this study was to monitor the dynamic process of these soluble factors in patients with cervical cancer at Taizhou Hospital of Zhejiang Province, trying to understand their relationship with diagnosis, treatment, and prognosis.. We quantified plasma levels of sHLA-G and 12 cytokines using ELISA and flow cytometry, respectively, in the peripheral blood of patients with cervical cancer divided into three groups: preoperation, postoperation and clinical relapse. Healthy women were used as the control group. Data were analysed by non-parametric tests, receiver-operating characteristic (ROC) curves, and Kaplan-Meier plotter (log-rank test).. In this study, our findings showed that preoperation plasma levels of sHLA-G and the cytokines IL-6, IL-10, and IFN-γ in cervical cancer patients had a good discriminatory effect between cervical cancer patients and healthy women. It should be noted that plasma levels of sHLA-G, IL-6, and IL-10 were significantly decreased within 30 days after radical hysterectomy (P < 0.05). A positive correlation was observed between IL-6 and IL-10, IL-8 and IL-17 levels preoperatively. In contrast, sHLA-G levels were negatively correlated with IL-10 but not with other cytokines. An increased survival rate in patients with cervical cancer was associated with IL-5 < 1.70 pg/mL, IL-17 < 2.30 pg/mL, and IFN-α < 2.26 pg/mL preoperatively. In addition, our findings showed that the levels of cytokines IL-6, IL-8, IL-12p70, IL-17, and IFN-γ may be related to 5-year relapse rates and/or the metastasis of cervical cancer.. The current findings enhance our understanding of the dynamic process (preoperation, postoperation and clinical relapse) of sHLA-G and these cytokines in the plasma of patients with cervical cancer from diagnosis to prognosis. These biomarkers may play a potential therapeutic target role of such dynamic changes in the immunotherapy for cervical cancer.

Topics: Cytokines; Female; HLA-G Antigens; Humans; Immunotherapy; Interleukin-10; Interleukin-17; Interleukin-6; Interleukin-8; Tumor Microenvironment; Uterine Cervical Neoplasms

The purpose of this experiment was to observe the biological effect and mechanism of miR-10b on cervical cancer (CC) rats. For this purpose, the rat model of CC was established and divided into three groups (Inhibitors/ Mimics/Control). The miR-10b transfection efficiency was analyzed via RT-PCR in cervical tissues in each group. The content of CD3+, CD4+, and CD8+ was detected. The levels of IL-8, TNF-β, IL-6, (CAT, SOD, and MDA were determined via ELISA, and the apoptosis of cervical tissues was detected usingTUNEL assay. The expressions of Caspase-3, Bcl-2, and the mTOR/P70S6K pathway genes and proteins were detected by qRT-PCR and Western blotting. Results showed that miR-10b was significantly increased in the Mimics group and decreased in the Inhibitors group. The content of IL-8, TNF-β, IL-6, CAT and MDA was raised, while that of SOD notably declined in the Inhibitors group. There were remarkably more apoptotic cells in the Mimics group, dominated by gliocytes, and fewer apoptotic cells in the Inhibitors group, with increased content of CD3+, CD4+ and CD8+. The Bcl-2, mTOR, and P70S6K mRNA expressions in the Inhibitors group were up-regulated than those in the other two groups, and the Caspase-3 gene in the Mimics group was increased and close to that in the control group. In the Mimics group, the mTOR and P70S6K protein were remarkably lower than those in the Inhibitors group. In conclusion, miR-10b can inhibit the occurrence and development of CC in rats by suppressing mTOR/P70S6K signaling, reducing the level of inflammation and oxidative stress, and increasing the level of immune factors.

Topics: Animals; Apoptosis; Caspase 3; Female; Interleukin-6; Interleukin-8; Lymphotoxin-alpha; MicroRNAs; Proto-Oncogene Proteins c-bcl-2; Rats; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Superoxide Dismutase; TOR Serine-Threonine Kinases; Uterine Cervical Neoplasms

Topics: Adult; Aged; Antagomirs; Apoptosis; Carcinoma; Cell Line, Tumor; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Humans; Interleukin-8; MicroRNAs; Middle Aged; Uterine Cervical Neoplasms

Interleukins-6 and -8 are two pro-inflammatory cytokines increasing in serum and local levels under malignant conditions. There are limited evidences on the association between cervical level of these two factors and cervical intraepithelial neoplasia (CIN). So, this study aimed to explore the association between cervical levels of IL-6 and IL-8 with cervical premalignant lesions.. The present case-control study was conducted on married women undergone Pap smear for routine screening in two groups as the group with CIN (n=100) and the healthy control group (n=100). Cervical secretions were collected using sterile swab and the levels of IL-8 and IL-6 were measured by enzyme-linked immunosorbent assay (ELISA). The obtained data were analyzed by SPSS software.. The mean cervical IL-6 level was 568.66±594.62 pg/ml in the patients with CIN and 212.7±213.9 pg/ml in the controls (P <0.001). The cervical IL-8 levels in the case and control groups were measured to be 1320.43±876.5 pg/ml and 1053.59±747.64 pg/ml, respectively (p=0.02). By modifying the confounding size effect of the age and marital duration, it was determined that cervical levels of IL-6 and IL-8 were both associated with CIN.. Our results showed that the cervical levels of IL-6 and IL-8 are associated with CIN independent of age and marital dura.

Topics: Adult; Age Factors; Case-Control Studies; Female; Humans; Interleukin-6; Interleukin-8; Iran; Marriage; Middle Aged; Papanicolaou Test; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; Young Adult

Cervical cancer as one of the most common malignant tumors lead to bad prognosis among women. Some researches already focus on the carcinogenesis and pathogenesis of cervical cancer, but it is still necessary to identify more key genes and pathways.. Differentially expressed genes were identified by GEO2R from the gene expression omnibus (GEO) website, then gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyzed by DAVID. Meanwhile, protein-protein interaction network was constructed by STRING, and both key genes and modules were found in visualizing network through Cytoscape. Besides, GEPIA did the differential expression of key genes and survival analysis. Finally, the expression of genes related to prognosis was further explored by UNLCAN, oncomine, and the human protein atlas.. Totally 57 differentially expressed genes were founded, not only enriched in G1/S transition of mitotic cell cycle, mitotic nuclear division, and cell division but also participated in cytokine-cytokine receptor interaction, toll-like receptor signaling pathway, and amoebiasis. Additionally, 12 hub genes and 3 key modules were screened in the Cytoscape visualization network. Further survival analysis showed that TYMS (OMIM accession number 188350), MCM2 (OMIM accession number 116945), HELLS (OMIM accession number 603946), TOP2A (OMIM accession number 126430), and CXCL8 (OMIM accession number 146930) were associated with the prognosis of cervical cancer.. This study aim to better understand the characteristics of some genes and signaling pathways about cervical cancer by bioinformatics, and could provide further research ideas to find new mechanism, more prognostic factors, and potential therapeutic targets for cervical cancer.

Topics: Biomarkers, Tumor; Computational Biology; DNA Helicases; DNA Topoisomerases, Type II; Female; Gene Regulatory Networks; Humans; Interleukin-8; Minichromosome Maintenance Complex Component 2; Poly-ADP-Ribose Binding Proteins; Protein Interaction Maps; Thymidylate Synthase; Transcriptome; Uterine Cervical Neoplasms

Gene expression and DNA methylation levels affect the outcomes of patients with cancer. The present study aimed to establish a multigene risk model for predicting the outcomes of patients with cervical cancer (CerC) treated with or without radiotherapy. RNA sequencing training data with matched DNA methylation profiles were downloaded from The Cancer Genome Atlas database. Patients were divided into radiotherapy and non‑radiotherapy groups according to the treatment strategy. Differently expressed and methylated genes between the two groups were identified, and 8 prognostic genes were identified using Cox regression analysis. The optimized risk model based on the 8‑gene signature was defined using the Cox's proportional hazards model. Kaplan‑Meier survival analysis indicated that patients with higher risk scores exhibited poorer survival compared with patients with lower risk scores (log‑rank test, P=3.22x10‑7). Validation using the GSE44001 gene set demonstrated that patients in the high‑risk group exhibited a shorter survival time comprared with the low‑risk group (log‑rank test, P=3.01x10‑3). The area under the receiver operating characteristic curve values for the training and validation sets were 0.951 and 0.929, respectively. Cox regression analyses indicated that recurrence and risk status were risk factors for poor outcomes in patients with CerC treated with or without radiotherapy. The present study defined that the 8‑gene signature was an independent risk factor for the prognosis of patients with CerC. The 8‑gene prognostic model had predictive power for CerC prognosis.

Topics: Adult; Disease-Free Survival; Female; Gene Expression Regulation, Neoplastic; Humans; Interleukin-8; Middle Aged; Models, Biological; Neoplasm Proteins; Predictive Value of Tests; Survival Rate; Uterine Cervical Neoplasms

inflammatory cytokines have been associated with various cancers, including cervical cancers. Interpreting cytokine expression in liquid based cervical samples is quite challenging. This study is aimed at evaluating the levels of interleukin 8 and 10 in liquid based cervical samples.. this is a descriptive analytical study carried out on eighty five (85) subjects aged between 23 and 68 years. Cervical samples were collected in liquid based medium and smears later examined after staining with Papanicolaou technique. These were categorized into low grade intra-epithelial lesion/malignancy, high grade intraepithelial lesion/malignancy according to the degree of dyskaryosis. Concentrations of interleukin 8 and interleukin 10 in the samples were determined by enzyme linked immunosorbent assay.. the mean age, standard deviation (SD) of the study subjects were 40.6 (7.8) years. A total number of 79 females (92.9%) were negative for intra-epithelial lesion/malignancy (NILM), while 4 (4.71%) and 2 (2.35%) were positive for low grade intra-epithelial lesion/malignancy (LILM) and high grade intra-epithelial lesion (HILM) respectively. While mean levels of interleukin 8 increased with the degree of malignancy, (107.27 ± 11.88pg/ml) in LILM, (114.80 ± 2.12pg/ml) in HILM when compared with NILM (88.39 ± 18.06pg/ml), (f = 0.700, p = 0.018); the mean levels of interleukin 10 was comparable between these groups (p ≥ 0.05). Pearson correlation coefficient analysis showed a negative association between interleukin 8 and interleukin 10 (r = -1.999, p = 0.000) in LILM.. interleukin 8 cytokines in cervical cancer is associated with the degree of malignancy. Possible anti-inflammatory effect of interleukin 10 was not observed.

Topics: Adult; Aged; Cervix Uteri; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-10; Interleukin-8; Middle Aged; Papanicolaou Test; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; Vaginal Smears; Young Adult

To explore whether cervical carcinoma cell-derived interleukin-27 (IL-27) modulates the angiogenesis of vascular endothelial cells.. The expression of IL-27 in cervical cancer tissues and cervical cell lines was analyzed by immunohistochemistry, ELISA and flow cytometry. Then, the effects of IL-27 on the proliferation and apoptosis-related molecules and angiogenesis in vitro of human umbilical vein endothelial cells (HUVECs) were investigated. Finally, in vivo experiment was performed to further confirm the effects of IL-27.. Compared with cervicitis, the cervical cancer tissues highly expressed IL-27. Both HeLa and CaSki cells secreted IL-27, and HUVECs expressed low levels of IL-27 receptors (IL-27R). However, the co-culture of cervical cell lines and HUVECs led to a significant elevation of IL-27R on HUVECs. Co-culturing with IL-27-overexpressed HeLa cells downregulated Ki-67 and Bcl-2 and upregulated Fas expression in HUVECs. In addition, overexpression of IL-27 in HeLa cells and CasKi cells secreted less IL-8 and could further restrict angiogenesis compared with control cells in vitro. In the subcutaneous tumorous model of C57/BL6 mouse, there were decreased vessel density and tumor volume when inoculation with IL-27-overexpressed TC-1 cells.. This study indicates that IL-27 secreted by cervical carcinoma cells restricts the angiogenesis in a paracrine manner in the pathogenesis of cervical cancer.

Topics: Animals; Apoptosis; Cell Proliferation; Coculture Techniques; Endothelial Cells; fas Receptor; Female; HeLa Cells; Human Umbilical Vein Endothelial Cells; Humans; Interleukin-27; Interleukin-8; Mice; Mice, Inbred C57BL; Neoplasms, Experimental; Neovascularization, Pathologic; Paracrine Communication; Proto-Oncogene Proteins c-bcl-2; Receptors, Interleukin; Uterine Cervical Neoplasms

Cysteine-X-cysteine ligand 8 (CXCL8) was originally discovered as a proinflammatory chemokine. Recently, CXCL8 has been shown to act as an oncogene in several types of human cancers. However, the clinical and prognostic significance of CXCL8 in cervical cancer is poorly understood. In our study, we found that CXCL8 was highly expressed in cervical cancer tissues compared with normal cervical tissues in microarray datasets (GSE9750 and GSE7803).

Topics: Adult; Biomarkers, Tumor; Cell Line, Tumor; Female; HeLa Cells; Humans; Interleukin-8; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Uterine Cervical Neoplasms

High-risk strains of human papillomavirus (HPV) are the causative agents of cervical and anogenital cancers and are associated with 5% of all human cancers. Although prophylactic vaccines targeting a subset of HPV types are available, they are ineffective in HPV-infected individuals. Elucidation of the mechanisms controlling HPV replication may allow development of novel anti-HPV therapeutics. Infectious HPV virions are produced during terminal differentiation of host cells. The process of viral maturation requires synergistic interactions between viral and cellular proteins that leads to amplification of the viral genome and expression of late viral genes. Here we show that the transcription factor Kruppel-like factor 13 (KLF13) has a critical role in the HPV life cycle. KLF13 is overexpressed in HPV-positive keratinocytes and cervical cancer cell lines. Expression of KLF13 in normal cervical epithelium is low but increases significantly in cervical intraepithelial neoplasia and invasive squamous cervical cancer. After HPV infection, the E7 protein suppresses ubiquitin ligase FBW7 expression leading to an increase in KLF13 expression. Reduction of KLF13 with short hairpin RNA in differentiating HPV-positive cells resulted in diminished levels of viral gene expression and genome amplification. Knockdown of KLF13 also reduced the level of the transcription factor signal transducer and activator of transcription 5, which led to the downregulation of the ataxia-telangiectasia mutated DNA damage pathway and the chemokine interleukin-8 (IL-8). In addition, neutralization of IL-8 diminished viral genome amplification in differentiating HPV-positive cells. Thus, KLF13 is critical for the activation of the HPV productive life cycle and is likely involved in initiation and progression of cervical cancer.

Topics: Animals; Ataxia Telangiectasia; Cell Cycle Proteins; Cell Differentiation; Cell Line; DNA Damage; F-Box Proteins; F-Box-WD Repeat-Containing Protein 7; Female; Gene Expression Regulation, Viral; Humans; Interleukin-8; Keratinocytes; Kruppel-Like Transcription Factors; Mice; Papillomaviridae; Papillomavirus Infections; Repressor Proteins; STAT5 Transcription Factor; Ubiquitin-Protein Ligases; Uterine Cervical Neoplasms; Virus Replication

Human papillomavirus (HPV) infections are strongly associated with the development of cervical intraepithelial neoplasias and invasive cervical cancer. Polymorphisms in cytokine-encoding genes and behavioural cofactors could play an important role in protecting an individual against viral infections and cancer. Here, we investigated whether IL-6 -174 G>C, IL-8 +396 G>T, and TGF-β1 +869 G>C and +915 G>C polymorphisms were associated with susceptibility to HPV infection in women from north-east (Pernambuco) Brazil. We analysed 108 healthy uninfected women (HC) and 108 HPV-positive women with cervical lesions. Genetic polymorphisms were assessed using Sanger sequencing and polymerase chain reaction-restriction fragment length polymorphism. Comparison of the distribution of the genotypic and allelic frequencies of the IL-18 +396 T>G polymorphism between HPV infected woman an uninfected controls showed that the GG genotype and G allele were both more frequent in the HC group, and were associated with protection from HPV infection (p = 0.0015; OR = 0.29 CI95% = 0.13-0.61; p = 0.0005; OR = 0.45 CI95% 0.29-0.7, respectively). Individuals from the control group could have previously had HPV infection that was spontaneously eliminated; however, it was undetectable at the time of sample collection. Based on our findings, we hypothesize that the IL-8 +396 G>T polymorphism could interfere with susceptibility to HPV infection, by modulating the ability of immune system to fight the virus.

Topics: Adolescent; Adult; Aged; Alleles; Base Sequence; Brazil; Cross-Sectional Studies; DNA, Viral; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Interleukin-6; Interleukin-8; Middle Aged; Papillomavirus Infections; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Transforming Growth Factor beta1; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; Young Adult

Immune responses in the uterine cervix are considered to play an important role in persistent human papillomavirus (HPV) infection and carcinogenesis, but many aspects of the mechanism are still unclear. The goal of this study was to measure cytokines to analyze immune responses in patients with cervical intraepithelial neoplasia (CIN).. The levels of 17 cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, G-CSF, GM-CSF, INF-γ, MCP-1, MIP-1β, and TNFα) in cervical mucus were simultaneously measured using a multiplex immunoassay in 52 high-grade squamous intraepithelial lesion (HSIL) cases and overproduction of IL-1β, IL-8, and MIP-1β was identified. The levels of these 3 cytokines were measured in 130 patients with or without CIN lesions using enzyme-linked immunosorbent assay. The associations of the cytokine levels with the cytology, infecting HPV type, and status of cigarette smoking were investigated.. IL-1β and IL-8 levels were associated with the cytology, and these levels were higher in HSIL cases than in NILM (negative for intraepithelial lesion and malignancy) and LSIL (low-grade squamous intraepithelial lesion) cases (P = 0.005, P = 0.001, respectively). The MIP-1β level was significantly lower in smokers (P = 0.018) and high-risk (HR)-HPV-infected patients (P = 0.021).. Enhanced expression of IL-1β and IL-8 indicates that Th2 inflammatory responses become stronger in the local uterine cervical region with the progression of CIN lesions, and a decrease in the MIP-1β level may be advantageous for immunoescape of HPV. Cigarette smoking may further facilitate persistent HPV infection.

Topics: Adult; Asian People; Chemokine CCL4; Disease Progression; Female; Humans; Interleukin-1beta; Interleukin-8; Mucous Membrane; Papillomavirus Infections; Smoking; Squamous Intraepithelial Lesions of the Cervix; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

Chemokines play a role in tumor-inflammation and angiogenesis that could be involved in tumor progression. Monocyte chemoattractant protein-1 (MCP-1), Interleukin-8 (IL-8) and macrophage inflammatory proteins (MIP) have been identified in tumor tissues of patients with different neoplasms. Therefore, the aim of the current study was to investigate the expressions of MCP-1, IL-8 and MIP-1α, mononuclear leukocyte infiltration and leukocyte/chemokine expressions in cervical tissues from patients with cervical intraepithelial neoplasia (CIN) and controls. MCP-1, IL-8 and MIP-1α expressions and leukocyte infiltration were determined by indirect immunofluorescence in cervix biopsies from CIN patients (n=65) and 7 normal controls. Increased expressions of MCP-1 and IL-8 in CIN were observed. Increment of lymphocyte infiltration and coexpression of CD3/MCP-1 and CD3/IL-8 were found in CIN. CD3/MCP-1 cell percentage was found decreased and CD3/IL-8 percentage increased according to the CIN evolution. MIP-1α remained similar to control values. The increased expression of MCP-1 and IL-8 in cervical neoplasia may lead to tumor progression.

Topics: Chemokine CCL2; Chemokine CCL3; Chemokines; Female; Humans; Interleukin-8; Leukocytes; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

Receptor activator for nuclear factor κB ligand (RANKL) is a member of the tumor necrosis factor (TNF) family. The interaction between RANKL and its receptor RANK plays an important role in the development and function of diverse tissues. However, the expression and role of RANKL in cervical cancer are still unknown. In the present study, we found that RANKL and RANK were highly co-expressed in cervical cancer. HeLa and SiHa cells secreted soluble RANKL (sRANKL), expressed member RANKL (mRANKL) and RANK. Recombinant human RANKL protein had no effect on the viability of HeLa and SiHa cells. Yet, blocking RANKL with an anti-human RANKL neutralizing antibody (α-RANKL) or recombinant human osteoprotegrin (OPG) protein resulted in the downregulation of Ki-67 and B-cell lymphoma 2 (Bcl-2) expression and an increase in Fas and Fas ligand (FasL) expression, as well as a high level of viability and a low level of apoptosis in the HeLa and SiHa cells. In addition, α-RANKL led to a decrease in IL-8 secretion. Recombinant human IL-8 protein reversed the effect of α-RANKL on the expression of proliferation- and apoptosis‑related molecules, and proliferation and apoptosis in the HeLa and SiHa cells. The present study suggests that a high level of mRANKL/RANK expression in cervical cancer lesions plays an important role in the rapid growth of cervical cancer cells possibly through strengthening the dialogue between cervical cancer cells and regulation of IL-8 secretion, which may be a possible target for cervical cancer therapy.

Topics: Antibodies, Neutralizing; Apoptosis; Cell Proliferation; Cell Survival; Fas Ligand Protein; Female; Gene Expression Regulation, Neoplastic; HeLa Cells; Humans; Interleukin-8; Osteoprotegerin; Proto-Oncogene Proteins c-bcl-2; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Recombinant Proteins; Uterine Cervical Neoplasms

To explore whether hypoxia and interleukin 8 (IL-8) regulate the viability and apoptosis of cervical carcinomas cells and the possible mechanism. We evaluated the expression of hypoxia inducible factor-1α (HIF-1α), IL-8 and its receptors (CXCR1 and CXCR2) in cervical cancer and cervicitis tissues by immunohistochemistry. Then the effects of hypoxia and IL-8 on the viability and apoptosis of HeLa and SiHa cells were detected by the SRB and apoptosis assays. Here we observed that the expression of HIF-1α, IL-8 and CXCR1 in cervical cancer tissues was significantly higher than that in cervicitis tissues. Hypoxic condition stimulated the secretion of IL-8 and the expression of CXCR1 and CXCR2 on HeLa and SiHa cells. Recombinant human IL-8 enhanced the viability and reduced the apoptosis in HeLa and SiHa cells. HeLa and SiHa cells cultured in 1% oxygen showed the increased viability and apoptosis, and the former effect could be partly reversed by anti-human IL-8 neutralizing antibody. This data suggested that IL-8 secreted by cervical carcinomas cells induced by hypoxia can stimulate the viability of cervical carcinomas cells in an autocrine dependent manner, and contribute to the pathogenesis of cervical cancer.

Topics: Antibodies, Neutralizing; Apoptosis; Autocrine Communication; Carcinoma, Squamous Cell; Cell Hypoxia; Cell Proliferation; Cell Survival; Female; HeLa Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Interleukin-8; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Recombinant Proteins; Signal Transduction; Up-Regulation; Uterine Cervical Neoplasms; Uterine Cervicitis

Our studies were conducted to investigate the clinical and functional significance of tumor-associated macrophages (TAMs) in cervical tumor lymphatic metastasis. We found that the increase in macrophages in tumor stroma is significantly associated with lymphatic metastasis (p = 0.017), through performing immunohistochemical staining in 111 cervical samples (55 invasive squamous carcinomas of uterine cervix, 27 cervical intraepithelial neoplasms III, and 29 normal cervix). The human lymphatic endothelial cells (HLEC), which were cultured in conditioned medium of cervical cancer cell-macrophage coculture, formed more tube-like structures in vitro, when compared with those in conditioned mediums of LEC, normal cervical epithelium, single macrophage, and single cervical cancer cell (all p < 0.001). The mRNA expressions of IL-1β and IL-8 in cervical cancer cells cocultured with macrophages were increased, compared with those in cervical cancer cell cultured alone (pIL-1β  < 0.05 and pIL-8  < 0.01). Meanwhile, the mRNA expression of VEGF-C and VEGF-A was increased in macrophages cocultured with cervical cancer cells, compared with the expression in those macrophages cultured alone (both p < 0.05). Taken together, the results suggest that TAMs promote lymphangiogenesis mainly through interaction with surrounding cervical cancer cells.

Topics: Cell Line, Tumor; Coculture Techniques; Endothelial Cells; Female; HeLa Cells; Humans; Immunohistochemistry; Interleukin-8; Lymphangiogenesis; Lymphatic Metastasis; Macrophages; Middle Aged; RNA, Messenger; Uterine Cervical Neoplasms; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor C

The objective was to study the effect of Scutellaria baicalensis Georgi ethanol extracts (SBGE) on immune and anti-oxidant function in U14 tumor-bearing mice.. U14 tumor-bearing mice were randomly divided into eight groups: a control group, a cyclophosphamide (CTX) group, three dose groups of SBGEI (high, medium, low), and three dose groups of SBGEII (high, medium, low). After two weeks, the thymus and spleen weight indices of mice bearing U14 cervical cancer were calculated. Enzyme linked immunosorbent assays (ELISA) was used to determine the levels of serum IL-2, TNF-α, IL-8, and PCNA. MDA activity and SOD activity in plasma were measured with detection kits.. In the SBGE groups, thymus weight and spleen weight indices of U14 tumor-bearing mice were significantly higher than in the control group or CTX group (p<0.05). Compared to control group, the levels of serum IL-2 and TNF-α in U14 tumor-bearing mice increased significantly, whereas the contents of serum IL-8 and PCNA decreased (p<0.05). The activity of SOD increased with the growing dose of SBGE, while the activity of MDA decreased significantly in the higher- dose groups of SBGE.. These findings suggested that SBGE, especially at high dose, 1000 mg/kg, showed significant immune and anti-oxidant effects in U14 tumor-bearing mice, which might be the mechanisms of SBGE inhibition of tumor growth.

Topics: Animals; Antioxidants; Cell Line, Tumor; Cyclophosphamide; Drugs, Chinese Herbal; Female; Interleukin-2; Interleukin-8; Medicine, Chinese Traditional; Mice; Phytotherapy; Plant Extracts; Proliferating Cell Nuclear Antigen; Scutellaria baicalensis; Spleen; Superoxide Dismutase; Thymus Gland; Tumor Necrosis Factor-alpha; Uterine Cervical Neoplasms

Tumor metastasis is a prominent cause of treatment failure in cervical carcinoma. Phenethyl isothiocyanate (PEITC) is an active component extracted from cruciferous plants that has exhibited anticancer activity in various types of human cancer; however, its effect on the inhibition of metastasis remains unclear. The current study aimed to explore the effect of PEITC on the suppression of metastasis in HeLa cervical carcinoma cells. Multiple variables were assessed with different methods as follows: Cell viability, with a Vi‑CELL analyzer; cell adhesion, by MTS assay; cell invasion, by Transwell assay; cell cycle, by flow cytometry assay; cytokine concentration, by ELISA assay; metastasis‑related gene and protein expression, by quantitative polymerase chain reaction and western blotting; and transcription factor activity, by gene reporter assay. The results indicated that PEITC exhibited an inhibitory effect on the adhesion and invasion of HeLa cells by induction of G2/M phase arrest, it reduced the expression of CDK1, MMP‑2/9, CD44, ICAM‑1, increased the production of TGF‑β, IL‑6 and IL‑8, and increased the phosphorylation of Smad2. These results suggest that PEITC may be a potential antitumor compound, acting through the TGF‑β/Smad2 pathway; and it has the potential for future use as a therapy for cervical carcinoma subsequent to further studies.

Topics: Antineoplastic Agents; Cell Adhesion; Cell Cycle Checkpoints; Cell Movement; Cell Proliferation; Drug Screening Assays, Antitumor; Female; Gene Expression; HeLa Cells; Humans; Interleukin-6; Interleukin-8; Isothiocyanates; Neoplasm Invasiveness; Neoplasm Metastasis; Signal Transduction; Smad2 Protein; Transforming Growth Factor beta; Uterine Cervical Neoplasms

Surgery and radiotherapy have been used for decades to treat cervical cancer; however, high recurrence and lymph node metastasis rates are observed after these procedures. New therapeutic agents are needed to improve survival rates of patients by reducing tumor growth and metastasis. We previously demonstrated that interleukin-8 (IL-8) was associated with lymph node metastasis of early cervical squamous cell carcinoma (SCC). The current study assessed the role of IL-8 in growth and metastasis of cervical SCC and evaluated the effects of targeting IL-8 with small hairpin RNA (shRNA) and a human anti-IL-8 antibody. The human cervical SCC cell lines CaSki (high IL-8 producers), SiHa, HeLa, and SiHa transfected with the IL-8 gene were used for the studies. IL-8 stimulated proliferation, migration, and invasion but prevented apoptosis of SCC cells in vitro. Suppressing IL-8 expression with shRNA reduced cell growth and invasion of SCC cells in vitro. In a xenograft model, SCC cells were inoculated subcutaneously into athymic mice to evaluate the effect of IL-8 and its antibody on tumor growth and metastasis and animal survival. IL-8 enhanced tumor growth and metastasis in vivo concomitant with reduced animal survival. IL-8 antibody treatment of tumor-bearing animals resulted in smaller tumor volume, decreased lymph node metastasis, and longer animal survival. Blockade of IL-8 with an antibody demonstrated significant anti-tumor effects in a xenograft model and may thus provide a potential alternative approach for the treatment of cervical cancer.

Topics: Animals; Antibodies; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Proliferation; Cyclin D1; Female; Gene Knockdown Techniques; HeLa Cells; Humans; Interleukin-8; Lymphatic Metastasis; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Nude; Neoplasm Transplantation; RNA, Small Interfering; Tumor Burden; Uterine Cervical Neoplasms; Xenograft Model Antitumor Assays

The expression of lysophosphatidic acid (LPA)-specific receptors in cervical cancer has not been clearly defined. In this study, we identified LPA1, LPA2 and LPA3 receptors' mRNA in SiHa, HeLa and CaSki cell lines by RT-PCR. These receptors were not associated with tumor cell proliferation in vitro. We then used a xenograph animal model to evaluate the effects of these receptors on in vivo cervical cancer tumorigenicity. When SiHa cells with different receptor expression patterns were seeded on the backs of SCID mice, the resulting knockout of both LPA2 and LPA3 significantly attenuated tumor growth; this decrease in tumor growth was found to be linked with decreased angiogenesis (microvessel density), suggesting that LPA2 and LPA3 are crucial for in vivo tumor growth through an angiogenic mechanism. We further investigated this mechanism of LPA receptor 2/3-mediated angiogenic capability by analyzing angiogenic factors in protein lysates from receptor knockout tumors, by detecting interleukin (IL-8) mRNA expression after treating with siRNA, by evaluating the biological role of LPA-enhanced IL-8 via endothelial cell tube formation, monolayer permeability, migration and cell growth assays, and by IL-8 knockout xenograft mice modeling. We found that the angiogenesis is mediated through IL-8. Finally, we evaluated the regulation pathways involved in LPA-induced IL-8 expression. We found that LPA receptor 2/3-mediated IL-8 expression occurs through Gi/PI3K/AKT, Gi/PKC and IκB/NF-κB signaling. In conclusion, we propose that LPA2 and LPA3 might play an important role in cervical cancer tumor growth through IL-8-dependent angiogenesis.

Topics: Base Sequence; Blotting, Western; Cell Line, Tumor; Culture Media, Conditioned; DNA Primers; Female; Humans; Immunoenzyme Techniques; Interleukin-8; Neovascularization, Pathologic; NF-kappa B; Phosphatidylinositol 3-Kinases; Protein Kinase C; Real-Time Polymerase Chain Reaction; Receptors, Lysophosphatidic Acid; RNA, Small Interfering; Signal Transduction; Uterine Cervical Neoplasms

Cervical cancer is one of the leading gynecological malignancies in women. We have recently shown that seminal plasma (SP) can regulate the inflammatory cyclooxygenase-prostaglandin pathway and enhance the growth of cervical epithelial tumours in vivo by promoting cellular proliferation and alteration of vascular function. This study investigated the molecular mechanism whereby SP regulates vascular function using an in vitro model system of HeLa cervical adenocarcinoma cells and human umbilical vein endothelial cells (HUVECs). We found that SP rapidly enhanced the expression of the angiogenic chemokines, interleukin (IL)-8 and growth regulated oncogene alpha (GRO) in HeLa cells in a time-dependent manner. We investigated the molecular mechanism of SP-mediated regulation of IL-8 and GRO using a panel of chemical inhibitors of cell signalling. We found that treatment of HeLa cells with SP elevated expression of IL-8 and GRO by transactivation of the epidermal growth factor receptor, activation of extracellular signal-regulated kinase and induction of cyclooxygenase enzymes and nuclear factor kappa B. We investigated the impact of IL-8 and GRO, released from HeLa cells after treatment with SP, on vascular function using a co-culture model system of conditioned medium (CM) from HeLa cells, treated with or without SP, and HUVECs. We found that CM from HeLa cells induced the arrangement of endothelial cells into a network of tube-like structures via the CXCR2 receptor on HUVECs. Taken together our data outline a molecular mechanism whereby SP can alter vascular function in cervical cancers via the pro-angiogenic chemokines, IL-8 and GRO.

Topics: Angiogenesis Inducing Agents; Blood Vessels; Chemokine CXCL1; Culture Media, Conditioned; Cyclooxygenase 1; Cyclooxygenase 2; Extracellular Signal-Regulated MAP Kinases; Female; Gene Expression Regulation, Neoplastic; HeLa Cells; Human Umbilical Vein Endothelial Cells; Humans; Interleukin-8; Male; Models, Biological; Phosphorylation; Semen; Signal Transduction; Up-Regulation; Uterine Cervical Neoplasms

Clinical studies demonstrate increased prevalence of human papillomavirus (HPV)-associated disease in HIV-infected individuals and an increased risk of HIV acquisition in HPV-infected individuals. The mechanisms underlying this synergy are not defined. We hypothesize that women with cervical intraepithelial neoplasia (CIN) will exhibit changes in soluble mucosal immunity that may promote HPV persistence and facilitate HIV infection.. The concentrations of immune mediators and endogenous anti-Escherichia coli activity in genital tract secretions collected by cervicovaginal lavage were compared in HIV-negative women with high-risk HPV-positive (HRHPV+) CIN-3 (n = 37), HRHPV+ CIN-1 (n = 12), or PAP-negative control subjects (n = 57).. Compared with control subjects, women with CIN-3 or CIN-1 displayed significantly higher levels of proinflammatory cytokines including interleukin (IL)-1α, IL-1β, and IL-8 (P < 0.002) and significantly lower levels of anti-inflammatory mediators and antimicrobial peptides, including IL-1 receptor antagonist, secretory leukocyte protease inhibitor (P < 0.01), and human β defensins 2 and 3 (P < 0.02). There was no significant difference in endogenous anti-E. coli activity after controlling for age and sample storage time.. HRHPV+ CIN is characterized by changes in soluble mucosal immunity that could contribute to HPV persistence. The observed mucosal inflammation suggests a mechanism that may also contribute to the epidemiologic link between persistent HPV and HIV.

Topics: Adolescent; Adult; Aged; Blotting, Southern; Cross-Sectional Studies; Cytokines; Escherichia coli; Female; Humans; Inflammation; Interleukin-1alpha; Interleukin-1beta; Interleukin-8; Middle Aged; New York; Papillomavirus Infections; Prevalence; Reproductive Tract Infections; Risk Factors; Therapeutic Irrigation; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; Young Adult

We observed diminished lymphoproliferation to multiple stimuli in older women with persistent cervical human papillomavirus (HPV) infection. Adipokines are a class of inflammatory cytokines that are altered in some persistent infections. The objective was to compare the level of adipokines and inflammatory cytokines in heparinized plasma from women with persistent HPV cervical infection (Cases, N=50, oversampled for their weak lymphoproliferation responses) with women with no evidence of persistent HPV cervical infection (Controls, N=50, oversampled for their strong lymphoproliferation responses). Plasma samples were analyzed with multiplex assays for adipokines and inflammatory cytokines. Cases had significantly elevated plasma levels of resistin (p<0.0001) and sFas (p=0.0038) as compared to controls. Risk of persistent HPV infection increased significantly with increasing levels of resistin and 8Fas. This is the first study to demonstrate elevated levels of resistin and sFas in HPV persistently infected, older women with decreased immune function expanding the understanding of the systemic inflammation and immune alterations in individuals persistently infected with HPV. Further studies within a larger cohort are needed to define the generalities of these findings and any role adipokines have in persistent HPV infection.

Topics: Adipokines; Alphapapillomavirus; fas Receptor; Female; Genotype; Humans; Inflammation Mediators; Interleukin-8; Middle Aged; Papillomavirus Infections; Resistin; Statistics, Nonparametric; Tumor Necrosis Factor-alpha; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

The IL-8 and MMP-7 genes participate in the carcinogenesis of many malignancies, but the role of both genes in cervical cancer is not fully elucidated. The aim of this study was to determine the frequency of IL-8 and MMP-7 gene mutations and to assess their effects on the risk of early stage cervical cancer and lymph node metastasis. The clinical stage and histological grade of cervical cancer were also studied. The peripheral blood from the patients with early stage cervical cancers and normal controls was collected and the DNA was extracted. The incidence of IL-8 and MMP-7 gene mutations was assessed by using tetra-primer amplification refractory mutation system polymerase chain reaction (ARMS PCR) and restriction fragment length polymorphism (RFLP). The data were statistically analyzed by x2 test. The results showed that: (1) The genotype frequency of IL-8 -251AT and TT was significantly higher in the cervical cancer group than in the normal control group (OR=2.290 and 2.619 respectively, P=0.001), and it was also higher in the lymphatic metastasis group than that without metastasis (OR=2.917, P=0.035); (2) The frequency of MMP-7 -181G/G genotype was significantly higher in the cervical cancer group and in the lymphatic metastasis group (P<0.05); (3) The incidence of IL-8 mutation was two times higher in IIa cervical cancer group than in Ib1 and Ib2 cervical cancer group (P=0.006). For the MMP-7 gene, there was statistically significant difference in the incidence of mutation between the Ib1, Ib2 and the IIa (P=0.000); (4) Different histological types and different grades of cervical cancer had different incidence of mutations, statistically. It was suggested that there was significant difference in the genotype of IL-8 -251TT and MMP-7 -181GG polymorphism between the cervical cancer group and the lymph node metastasis group. Moreover, individuals with IL-8 T allele or MMP-7 G allele carriers were at significantly higher risk of cervical cancer, particularly the early (IIa) and medium, poorly differentiated cervical cancer (G2+G3).

Topics: Adult; Aged; Alleles; China; Female; Genotype; Humans; Interleukin-8; Lymphatic Metastasis; Matrix Metalloproteinase 7; Middle Aged; Mutation; Polymorphism, Genetic; Risk Factors; Uterine Cervical Neoplasms

To evaluate the local immune response in patients with bacterial vaginosis (BV) and cervical intraepithelial neoplasia (CIN), as assessed by cytokine and nitric oxide (NO) concentrations.. Patients attending for routine gynaecological examination were prospectively enrolled in groups: BV (n=25) diagnosed by clinical criteria, CIN graded I to III (n=35, 6 CIN I, 8 CIN II and 21 CIN III) by histological analysis, and controls (n=15) without clinical and cytological findings. Randomly selected patients within CIN group at grades II or III (n=15) were re-evaluated at 60 days after surgical treatment. Endocervical (EC) and vaginal secretion samples were collected by cytobrush and the levels of cytokines (ELISA) and NO metabolite (Griess reaction) were assayed.. NO was assessed in all subjects, and cytokines in all controls, 15 BV and 30 CIN patients. Interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10) and nitrite levels were higher in EC than in vaginal secretions in BV and CIN groups. In CIN group, IL-8, IL-10 and nitrite concentrations were greater in EC and/or vaginal secretions than in BV or controls. Surgical treatment reduced IL-8 levels in EC and vaginal secretions.. A similar local immune profile was found in BV and CIN groups. The increased local production of IL-8, IL-10 and NO in CIN suggests a role for these mediators in the immune response against tumour or tumour development.

Topics: Adolescent; Adult; Bodily Secretions; Cervix Uteri; Cytokines; Female; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Middle Aged; Nitric Oxide; Prospective Studies; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; Vagina; Vaginosis, Bacterial

Angiogenesis is essential for the development, growth and advancement of solid tumors. Angiogenesis is induced by hypoxia with angiogenic transcription factor hypoxia inducible factors (HIF). This prompted us to study the clinical implications of HIF relative to angiogenesis in uterine cervical cancers. Although there was no significant difference in HIF-1alpha histoscores and mRNA levels according to histopathological type or lymph node metastasis, HIF-1alpha histoscores and mRNA levels increased significantly with advancing cancer stages. The prognosis of 30 patients with high HIF-1alpha in uterine cervical cancers was poor (73% survival), whereas the 24-month survival rate of the other 30 patients with low HIF-1alpha was 93%. HIF-1alpha histoscores and mRNA levels were correlated with the levels of the angiogenic factors thymidine phosphorylase and interleukin-8, and HIF-1alpha might be linked with these factors in cervical cancer tissue. HIF-1alpha is a candidate for prognostic indicator as an angiogenic mediator in uterine cervical cancer.

Topics: Adult; Aged; Apoptosis; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; In Situ Nick-End Labeling; Interleukin-8; Lymphatic Metastasis; Middle Aged; Neoplasm Staging; Neovascularization, Pathologic; Prognosis; Protein Isoforms; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Survival Analysis; Thymidine Phosphorylase; Uterine Cervical Neoplasms

Immunological status, levels of pro-inflammatory cytokines of non-specific resistance and tumor expression factor have been studied in patients with cervical dysplasia or cancer versus stage. Slight and moderate dysplasia involved virtually no changes in interleukin-8 (Il-8) and tumor necrotic factor TNF-alpha concentrations whereas those of Il-1 alpha and Il-1 beta were 5 times as high. Monocyte-dependent expression of tissue factor was similar to that in healthy women. In cases of advanced dysplasia and cervical carcinoma, monocyte-dependent expression of tissue factor and production of Il-1 alpha, Il-1 beta, Il-8 and TNF-alpha were significantly enhanced. Patients with cervical carcinoma stage II and III revealed signs of depression of the cellular component of immunity as well as non-specific resistance. Hence, increased concentrations of cytokines induce monocyte-dependent expression of tissue factor in advanced dysplasia and cervical carcinoma by triggering-on of hypercoaggulation.

Topics: Adult; Cytokines; Female; Gene Expression Regulation, Neoplastic; Humans; Interleukin-1; Interleukin-8; Middle Aged; Neoplasm Staging; Thrombophilia; Thromboplastin; Tumor Necrosis Factor-alpha; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

There was a significant correlation between microvessel counts and interleukin (IL)-8 levels and between infiltrated macrophage counts and IL-8 levels in uterine cervical cancers. Immunohistochemical staining revealed that the localization of IL-8 was similar to that of CD68 for macrophages. The prognosis of the 20 patients with high IL-8 (>1000 pg/mg protein) in uterine cervical cancers was extremely poor, whereas the 24-month survival rate of the other 60 patients with low IL-8 (<1000 pg/mg protein) was 67%. Therefore, this indicates that IL-8 might be a prognostic indicator as an angiogenic factor supplied from macrophages within and around the tumor.

Topics: Adenocarcinoma; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Female; Humans; Immunoenzyme Techniques; Interleukin-8; Macrophages; Neovascularization, Pathologic; Prognosis; Survival Rate; Uterine Cervical Neoplasms

Cellular immunity plays a major role in controlling human papilloma virus infection and development of cervical carcinoma. Mononuclear cell infiltration possibly due to the action of chemokines becomes prominent in the tumor tissue. In fact, the macrophage chemoattractant protein-1, MCP-1, was detected in cervical squamous cell carcinoma in situ, whereas absent in cultured cells. From this, unknown environmental factors were postulated regulating chemokine expression in vivo. In this study, we show high CD40 expression on cervical carcinoma cells and CD40 ligand (CD40L) staining on attracted T cells in tumor tissue, suggesting a paracrine stimulation mechanism via CD40L-CD40 interactions. We therefore investigated chemokine synthesis in nonmalignant and malignant human papilloma virus-positive cell lines after CD40L exposure. Constitutive expression of MCP-1, MCP-3, RANTES, and IFN-gamma-inducible protein-10 was almost undetectable in all cell lines tested. CD40L was able to induce MCP-1 production; however, despite much higher CD40 expression in malignant cells, MCP-1 induction was significantly lower compared with nontumorigenic cells. After sensitization with IFN-gamma, another T cell-derived cytokine showing minimal effects on CD40 expression levels, CD40 ligation led to a more than 20-fold MCP-1 induction in carcinoma cell lines. An even stronger effect was observed for IFN-gamma-inducible protein-10. Our study highlights the synergism of T cell-derived mediators such as CD40L and IFN-gamma for chemokine responses in cervical carcinoma cells, helping to understand the chemokine expression patterns observed in vivo.

Topics: Carcinoma, Small Cell; CD40 Antigens; CD40 Ligand; Cell Line, Transformed; Cell Transformation, Neoplastic; Chemokine CCL2; Chemokine CXCL10; Chemokines; Chemokines, CXC; Drug Synergism; Female; Humans; Interferon-gamma; Interleukin-8; Keratinocytes; Ligands; Membrane Glycoproteins; NF-kappa B; Papillomaviridae; Papillomavirus Infections; Protein Binding; Tumor Cells, Cultured; Uterine Cervical Neoplasms

Conflicting data exist on IL-6 production by human papillomavirus (HPV) immortalized cell lines and several cervical carcinoma cell lines. However, no information has been reported on the levels of cytokines in cervicovaginal washings in relation to cervical neoplasia. The aim of this study was to investigate whether local production of IL-6 could be found and whether the level of this cytokine was related to the severity of cervical neoplasia. IL-8 was measured to obtain additional information on an inflammatory cytokine with possible epithelial origin.. Cervicovaginal washings and sera were obtained from 35 patients with invasive cervical cancer, 62 patients with cervical intraepithelial neoplasia (CIN), and 25 control subjects. IL-6 and IL-8 levels were determined by ELISA. HPV DNA in cervical smears was detected by a HPV-16-specific PCR method and additionally by CPI/IIG PCR. Histological analysis of the inflammatory infiltrate was performed on hematoxylin-eosin-stained tissue sections.. In the patients with cervical cancer, those with CIN, and the controls, the median IL-6 concentration in cervicovaginal washings was 171 pg/ml (interquartile range: 54-780), 22 pg/ml (<2-73), and < 2 pg/ml (<2-<2), respectively. For IL-8, the levels were 2756 pg/ml (1651-7107), 489 pg/ml (248-1158), and 631 pg/ml (346-897), respectively. In most subjects the local levels were much higher than in serum. Local IL-6 and IL-8 levels were significantly higher in patients with cervical carcinoma compared with CIN patients and controls. Likewise, local IL-6 levels were increased in patients with CIN compared with controls. No relation was found between cytokine levels and CIN grade or between cytokine levels and the inflammatory infiltrate scored by histological analysis.. There is local production of IL-6 and IL-8 in cervicovaginal secretions, and the production of IL-6 was related to the severity of cervical neoplasia.

Topics: Adult; Aged; Carcinoma; Cervix Mucus; Female; Humans; Interleukin-6; Interleukin-8; Middle Aged; Uterine Cervical Neoplasms; Vagina

Interleukin (IL) 17 is a proinflammatory cytokine secreted mainly by activated human memory CD4 T cells that induces IL-6, IL-8, and nitric oxide. Because IL-6 and IL-8 have been implicated in the pathogenesis of cervical cancer, we investigated the action of IL-17 on human cervical tumor cell lines in vitro and in vivo. We showed that in vitro, IL-17 increases IL-6 and IL-8 secretion by cervical carcinoma cell lines at both protein and mRNA levels. No direct effect of IL-17 on in vitro proliferation of cervical tumor cell lines could be demonstrated. However, two cervical cell lines transfected with a cDNA encoding IL-17 exhibited a significant increase in tumor size as compared to the parent tumor when transplanted in nude mice. This enhanced tumor growth elicited by IL-17 was associated with increased expression of IL-6 and macrophage recruitment at the tumor site. A potential role of IL-17 in modulation of the human cervical tumor phenotype was also supported by its expression on the cervical tumor in patients with CD4 infiltration. IL-17 therefore behaves like a T-cell-specific cytokine with paradoxical tumor-promoting activity. This may partially explain previous reports concerning the deleterious effect of CD4 T cells in cancer.

Topics: Animals; Carcinogens; CD4-Positive T-Lymphocytes; Female; Gene Expression Regulation, Neoplastic; HeLa Cells; Humans; Interleukin-17; Interleukin-6; Interleukin-8; Male; Melanoma; Mice; Mice, Nude; Neoplasm Proteins; Neoplasm Transplantation; Recombinant Fusion Proteins; Reverse Transcriptase Polymerase Chain Reaction; T-Lymphocytes; Transfection; Tumor Cells, Cultured; Uterine Cervical Neoplasms

A novel human cell line, TOM-2, was established from a rare uterine cervical cancer, glassy cell carcinoma (GCC). TOM-2 is the second established GCC cell line so far reported. The cells were intermediately or poorly differentiated with dysplastic nuclei and polygonal shape and secreted two tumor markers and cytokines, i.e., CA-125 and SCC, interleukin (1L)-1alpha, -6, and -8, and TNF-alpha. Growth of TOM-2 was so strongly dependent on population density that it was not possible to determine the plating efficiency. In mass culture, the following characteristics were observed: doubling time, 83 h; mode of chromosome number, 79; human papillomavirus type 18 DNA, detectable; tumorigenicity, easily transplantable into subcutis of nude mice; chemosensitivity in vitro, considerably sensitive to Cisplatin and 5-FU but not to 9 other antineoplastic agents. This novel cell line will be useful for developing new therapeutic strategies for the rare cancer, GCC.

Topics: Adult; Animals; Antineoplastic Agents; Carcinoma, Adenosquamous; Cell Division; Cervix Uteri; Chromosomes; DNA, Viral; Female; HeLa Cells; Humans; Interleukin-6; Interleukin-8; Isoenzymes; L-Lactate Dehydrogenase; Mice; Mice, Inbred BALB C; Mice, Nude; Mycoplasma; Papillomaviridae; Purine-Nucleoside Phosphorylase; Tumor Cells, Cultured; Uterine Cervical Neoplasms