Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This report characterizes nine new cell lines derived from patients with malignant pleural mesothelioma. The lines were initiated between July 1990 and July 1992 from solid tumors (5 lines) or effusions (4 lines) and had proliferated for a period of at least 2 months without senescence. They were characterized by cell size, doubling time, immunohistochemical analyses, electron microscopy, and chromosomal karyotyping. Growth factor/cytokine elaboration was determined using enzyme-linked immunoassays. The established lines were similar in morphology to their parent tumor (ie, epithelial or sarcomatoid). Cell sizes ranged from 59 to 81 microns, and the doubling times varied from 31 to 65 hours. The lines stained with cytokeratin and showed expected negative staining for adenomarkers including B72.3 and carcinoembryonic antigen. All cell lines exhibited aneuploidy, with modal chromosome numbers between 40 and 81 and had multiple chromosomal aberrations. Significant production of granulocyte-monocyte colony-stimulating factor, leukemia inhibitory factor, platelet-derived growth factor, and interleukin-6 was seen. These new cell lines derived from human mesotheliomas can now be used to aid in the design of innovative treatment strategies.
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PMID:Characteristics of nine newly derived mesothelioma cell lines. 769 6

A role for interleukin-6 (IL-6) in malignant mesothelioma has been suggested by the clinically presenting symptoms of mesothelioma patients, which include fever, weight loss and thrombocytosis. A murine model of malignant mesothelioma was therefore used to examine the potential role of IL-6 in this cancer type and whether the effect of interferon alpha (IFN alpha) therapy on mesothelioma might be mediated, in part, by regulating IL-6 levels and/or IL-6-induced pathobiology. A panel of human and murine mesothelioma cell lines was assayed for endogenous IL-6 production in a bioassay, and for IL-6-mRNA expression. Four out of 5 human and 5 out of 15 murine mesothelioma cell lines produced moderate to high levels of bioactive IL-6 in vitro. This result was corroborated by mRNA detection. One of the representative murine cell lines, AB22, was chosen for further in vivo studies in the murine mesothelioma model. In AB22-inoculated mice detectable serum IL-6 levels were found to precede macroscopically detectable tumour growth, clinical signs (cachexia, abdominal distension, diarrhoea) and changes in the peripheral lymphoid organs (cell depletion and functional depression). Treatment with anti-IL-6 antibody curtailed the clinical symptoms (P < 0.001), as did treatment with recombinant human (rhu) IFN alpha (P < 0.001). Neither anti-IL-6 antibody nor rhuIFN alpha had a direct growth-inhibitory effect on the AB22 mesothelioma cell line in vitro, however, in vivo rhuIFN alpha treatment of mice inoculated with AB22 cells attenuated both IL-6 mRNA expression in the tumours and serum IL-6 levels, ameliorated the depression of lymphocyte activities, and enhanced the number of tumour-infiltrating lymphocytes and macrophages. On the basis of these results it is suggested that IL-6 mediates some of these effects, directly or indirectly, and that a combination therapy of rhuIFN alpha and anti-IL-6 antibody may be an improved palliative treatment for patients with malignant mesothelioma.
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PMID:Interleukin-6 involvement in mesothelioma pathobiology: inhibition by interferon alpha immunotherapy. 775 Jan 22

A mesothelioma cell line, termed T-85, was established from a patient with malignant peritoneal mesothelioma and remarkable thrombocytosis (1.4 x 10(6)/mm3). Electron microscopically, two types of mesothelioma cells have been characterized; the major type of cells with dense-cored granules in the cytoplasm and the minor one with evenly dense granules. Immunologically, the cells showed staining for interleukin-6 (IL-6), cytokeratin, collagen type IV, vimentin, laminin, fibronectin and Factor VIII-related antigen. Quantitation by ELISA revealed a high concentration of IL-6 in T-85 cell culture supernatants. RT-polymerase chain reaction of T-85 cells showed two positive bands of cDNA at 628 and 251 base pairs indicating the constitutive expression of IL-6 and IL-6 receptor mRNA. Moreover, prominent pro-platelet process formation activity in T-85 cell culture supernatants indicated the presence of a thrombopoietic activity due mainly to IL-6 but not the c-Mpl ligand or erythropoietin. However, the fact that 15% of PPF activity remained in the supernatants treated with anti-IL-6 antibody indicated the presence of another thrombopoietic substance. T-85 is so far the first mesothelioma cell line derived from a case with remarkable thrombocytosis.
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PMID:Establishment and characterization of a new human mesothelioma cell line (T-85) from malignant peritoneal mesothelioma with remarkable thrombocytosis. 887 1

We report the unusual occurrence of Kaposi's sarcoma following asbestos-related malignant mesothelioma, in a human deficiency virus (HIV)-negative Italian man. Seropositivity to human herpes virus 8 (HHV8) was documented at the time of mesothelioma diagnosis and preceded the onset of Kaposi' sarcoma with a time lapse of 13 months. HHV8 DNA was detected by polymerase chain reaction in lesional Kaposi's sarcoma but not within mesothelioma. By immunostaining, mesothelioma cells expressed interleukin-6 and platelet-derived growth factor, which are important for survival of Kaposi's sarcoma cells. Besides the possibility of a casual association, we hypothesize that mesothelioma-linked factors may have contributed to the development of Kaposi's sarcoma in the presence of HHV8 infection.
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PMID:Kaposi's sarcoma following malignant mesothelioma. 1062 4

After the recognition of human herpes virus 8 (HHV-8) in Kaposi's sarcoma lesions, this new virus has been shown to be associated with various types of malignancy. One of them, body cavity-based lymphoma, is a high grade B-cell lymphoma arising from the body cavities. Similarly, mesothelioma is a tumour that originates from the serosal linings of the pleural, pericardial and peritoneal cavities. One of the striking characteristics of mesothelioma cells is the secretion of interleukin-6 (IL-6). Also, it is known that HHV-8 upregulates the levels of IL-6, and this virally originated IL-6 is a well-established growth factor for HHV-8-associated lesions. Therefore, it was hypothesized that HHV-8 may have a role in the pathogenesis of malignant mesothelioma. Twenty-nine pleural biopsy specimens from environmentally induced malignant mesothelioma patients were investigated for the presence of HHV-8 deoxyribonucleic acid (DNA) using the polymerase chain reaction (PCR). Control pleural samples were collected from 15 biopsy specimens from patients with tuberculosis. From all samples, a segment of the beta-globulin gene was amplified in order to make sure that the DNA was extracted properly and did not contain any inhibitors. The specificity of the PCR amplification was confirmed by means of restriction enzyme analysis using Providencia stuartii I. PCR did not reveal HHV-8 DNA in any of the mesothelioma patients or in the control group. It was possible to amplify a segment of the human beta-globulin gene from all the samples of the patient and control groups. HHV-8 DNA was amplified in the control sample, which was a tissue biopsy specimen from a Kaposi's sarcoma lesion, and it was confirmed that the amplified DNA belonged to HHV-8 by restriction enzyme analysis. Malignant mesothelioma continues to be a public health problem in rural parts of Anatolia, Turkey. The major causal factor of the disease is exposure to asbestos and fibrous zeolite (erionite). It seems that there must be some aetiological factors other than exposure to these minerals as not all patients exposed to asbestos develop the disease and the disease is not always associated with any known exposure. From the present study, it was concluded that human herpes virus 8 does not seem to be associated with environmentally induced malignant mesothelioma in Turkey. Other possible causal factors of malignant mesothelioma should be sought.
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PMID:HHV-8 is not a cofactor in the pathogenesis of environmentally induced malignant pleural mesothelioma. 1094 69

An autopsy case of granulocyte colony-stimulating factor (G-CSF)- and interleukin-6 (IL-6)-producing diffuse deciduoid peritoneal mesothelioma is reported. The patient was a 70-year-old man with abdominal distension and weight loss in the year prior to his death. Laboratory data suggested severe inflammation with marked leukocytosis, thrombocytosis and elevated serum levels of C-reactive protein, G-CSF and IL-6. Imaging studies showed an expansive mass occupying the entire abdomen and pelvic cavity. Histological diagnosis of tissue taken by needle biopsy was difficult due to the unusual sarcomatoid-appearance of the tumor. In addition, there was severe infiltration of numerous neutrophilic leukocytes. An autopsy revealed that the diffuse peritoneal tumor had a fresh fishmeat-like appearance with focal mucinous degeneration and entirely encased the abdominal organs. Histological examination showed a sheet-like proliferation of tumor cells with large ovoid or polygonal cytoplasm, large atypical nuclei and obvious nucleoli. The tumor cells showed abundant glycogen and hyaluronic acid, and were immunoreactive to cytokeratin, calretinin, epithelial membrane antigen (EMA), CA-125, and focally to vimentin. The tumor cells were immunoreactive to G-CSF and IL-6. Electron microscopy revealed long, slender microvilli on the tumor cell surface. This tumor was diagnosed as a G-CSF- and IL-6-producing, diffuse deciduoid mesothelioma. We report this case with special reference to the differential diagnosis of deciduoid peritoneal mesothelioma with paraneoplastic syndrome.
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PMID:Granulocyte-colony stimulating factor- and interleukin 6-producing diffuse deciduoid peritoneal mesothelioma. 1530 18

5,6-Dimethylxanthenone-4-acetic acid (DMXAA) is a small molecule in the flavanoid class that has antitumor activity thought to be due to ability to induce high local levels of tumor necrosis factor (TNF)-alpha that disrupt established blood vessels within tumors. The drug has completed phase 1 testing in humans and is currently in phase 2 trials in combination with chemotherapy. Although characterized as a "vascular disrupting agent," there are some studies suggesting that DMXAA also has effects on the immune system that are important for its efficacy. The goal of this study was to carefully define the immune effects of DMXAA in a series of murine lung cancer and mesothelioma cell lines with varying immunologic characteristics. We show that DMXAA efficiently activated tumor-associated macrophages to release a variety of immunostimulatory cytokines and chemokines, including TNF-alpha; IFN-inducible protein-10; interleukin-6; macrophage inflammatory protein-2; monocyte chemotactic protein-1; and regulated on activation, normal T-cell expressed, and secreted. DMXAA treatment was highly effective in both small and large flank tumors. Animals cured of tumors by DMXAA generated a systemic memory response and were resistant to tumor cell rechallenge. DMXAA treatment led to initial tumor infiltration with macrophages that was followed by an influx of CD8(+) T cells. These CD8(+) T cells were required for antitumor efficacy because tumor inhibitory activity was lost in nude mice, mice depleted of CD8(+) T cells, and perforin knockout mice, but not in CD4(+) T-cell-depleted mice. These data show that activation of tumor-associated macrophages by DMXAA is an efficient way to generate a CD8(+) T-cell-dependent antitumor immune response even in animals with relatively nonimmunogenic tumors. Given these properties, DMXAA might also be useful in boosting other forms of immunotherapy.
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PMID:Activation of tumor-associated macrophages by the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid induces an effective CD8+ T-cell-mediated antitumor immune response in murine models of lung cancer and mesothelioma. 1635 88

Malignant mesothelioma (MM), an incurable tumor, is reportedly an interleukin-6 (IL-6) secreting tumor. The pathological significance of IL-6 overexpression in this tumor, however, has remained unclear. We investigated the biological functions of IL-6 in mesotheliomas. Five mesothelioma cell lines were analyzed for IL-6 production and IL-6 receptor (IL-6R) expression. Of them, 2 produced high levels of IL-6, 2 produced intermediate levels and 1 cell line showed no secretion. All mesothelioma cell lines used in this study expressed very small amounts of IL-6R mRNA. We compensated for this low level of IL-6R expression in mesotheliomas by adding recombinant soluble IL-6R (sIL-6R) to mediate the IL-6 signal. IL-6 together with sIL-6R was found to promote cell growth of H2052 and H226 MMs classified as high-level IL-6 producers in a dose-dependent manner. Moreover, a humanized anti-IL-6R antibody (MRA) capable of blocking IL-6 signaling suppressed the cell growth of mesotheliomas induced by IL-6/sIL-6R. These findings demonstrate that IL-6 serves as an autocrine growth factor in the development of mesothelioma. In addition, IL-6/sIL-6R stimulation increased the expression of vascular endothelial growth factor (VEGF) in 4 out of 5 cell lines, and this induction was inhibited by MRA treatment. The involvement of the signal transducer and activator of transcription 3 (STAT3) pathway in both cell growth and VEGF induction by IL-6/sIL-6R was verified by dominant negative STAT3 transduction combined with adenovirus gene-delivery methods. Although IL-6 induces VEGF through the JAK2/STAT3 pathway, anti-VEGF antibody could not inhibit the IL-6-induced cell growth observed in H2052 and H226. We concluded that IL-6-dependent growth does not occur via VEGF induction. These results suggest that treatment with anti-IL-6R antibody may constitute a potential molecular targeting therapy for MMs.
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PMID:Interleukin-6 induces both cell growth and VEGF production in malignant mesotheliomas. 1664 74

Although the insulating properties of asbestos have been known for millennia, the link between asbestos exposure and mesothelioma was not recognized until 1960, when it was first described in South African asbestos miners. The incidence of mesothelioma parallels asbestos usage with a latency of 20 to 40+ years; thus, patient numbers are declining in the United States but rising in the developing world. Radiation, genetics, and possibly simian virus 40 are less common causes. Diagnosis can be challenging, since the results of pleural fluid cytology testing are often negative despite repeated sampling. No staging system adequately predicts prognosis in the unresected patient. Newly described biomarkers, including soluble mesothelin-related peptide, megakaryocyte potentiation factor, and osteopontin, may predict which asbestos-exposed individuals will develop mesothelioma, and may prove useful in assessing response to treatment. Since surgery cannot eradicate all residual microscopic disease, a multimodality approach is encouraged. Metaanalysis suggests that pleurectomy/decortication may achieve outcomes similar to those of extrapleural penumonectomy. The standard first-line chemotherapy for unresectable disease is pemetrexed plus cisplatin. This combination improves response, survival, time to progression, pulmonary function, and disease-related symptoms. Carboplatin is often substituted, with similar results. Other active agents include raltitrexed, gemcitabine, and vinorelbine. Novel agents in clinical trials include inhibitors of the epidermal growth factor receptor, vascular endothelial growth factor, mesothelin, and histone deacetylases. Although disappointing results of early trials did not confirm promising preclinical data, recent studies have suggested that some novel agents may be effective. As we learn more about mesothelioma biology, molecularly targeted agents may become treatment options.
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PMID:Malignant pleural mesothelioma: an update on biomarkers and treatment. 1973 92

Malignant mesothelioma (MM) still remains a dismal disease with a median overall survival between 9-12 months. During the past decade since the introduction of the multi-folate antagonist, pemetrexed, there have been no significant advances in its systemic treatment, particularly with novel therapeutics that have exhibited varying degrees of success in other solid tumours. In recent years, the pleiotropic proinflammatory cytokine, interleukin-6 (IL-6) has emerged as a mediator of pivotal processes such as cell proliferation and chemoresistance within the mesothelioma tumour microenvironment in addition to clinical symptoms commonly witnessed in this disease. This manuscript provides a brief summary on the pathophysiology and clinical management of MM, followed by the role of IL-6 in its tumourigenesis and the rationale for utilising anti-IL-6 therapeutics alongside standard chemotherapy and targeted agents in an attempt to prolong survival.
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PMID:The role of interleukin-6 in malignant mesothelioma. 2580 46


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