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)

Human immunodeficiency virus (HIV)-1 infection is associated with increased frequency of Kaposi's sarcoma and high-grade B-cell lymphoma. Several other cancers in HIV-1-infected individuals have been reported, although without statistically significant increase in their respective occurrences. Although HIV-1 does not infect either Kaposi's sarcoma-derived spindle cells or B lymphocytes in vivo, viral proteins in vitro have been shown to be mitogenic to both Kaposi's sarcoma-derived spindle cells and B lymphocytes. Furthermore, several cytokines influence directly and indirectly the proliferative differentiation capacity of these cells. These cytokines include interleukin-1, interleukin-4, interleukin-6, and tumor necrosis factor. Many of these cytokines also are regulated by HIV-1 infection of T lymphocytes and monocyte/macrophage. Furthermore, elevated levels of interleukin-1, interleukin-6 and tumor necrosis factor have been observed in patients with HIV-1 infection, particularly in advanced stages, when these tumors often manifest. Thus, it appears that although HIV-1 does not directly transform cells permissive to its infection, viral proteins directly and through regulation of cellular genes exert activities that may lead to the development of Kaposi's sarcoma and B-cell lymphoma.
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PMID:Pathogenesis of HIV-related malignancies. 175 80

The use of inhibiting cytokine-binding-proteins (CBPs) such as soluble cytokine receptors and anticytokine antibodies is considered for the treatment of cytokine-dependent diseases. The pleiotropic cytokine interleukin-6 (IL-6) is a target for immunointervention in numerous pathologic situations, including multiple myeloma, B-cell lymphoma, and rheumatoid arthritis. An antitumor response was obtained in the treatment of a patient with multiple myeloma. A controversial issue is to evaluate whether the carrier effect of the CBPs might limit their efficiency in blocking the target cytokine. We analyzed the pharmacokinetics of radiolabeled IL-6 in mice treated with various combinations of anti-IL-6 antibodies. We show that injection of one or two antibodies led to the stabilization of the cytokine. Conversely, simultaneous treatment with three anti-IL-6 antibodies, binding to three distinct epitopes, induced the rapid uptake of the trimeric immune complexes by the liver and the elimination of IL-6 from the central compartment. The use of cocktails of three antibodies binding simultaneously to a cytokine thus provides a new means of enhancing the clearance of the target molecule and should help in the design of antibody-based clinical trials by overcoming the problem of the accumulation of the cytokine in the form of monomeric immune complexes.
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PMID:Pharmacokinetic study of anti-interleukin-6 (IL-6) therapy with monoclonal antibodies: enhancement of IL-6 clearance by cocktails of anti-IL-6 antibodies. 784 13

Despite improved procedures in chemotherapy and bone marrow transplantation (BMT), post-BMT leukemia relapse rates have remained rather constant in the last decade. Immunotherapy with monoclonal or bispecific antibodies (bsAb) is a promising approach to improve this situation, but is hampered by the absence of tumor-specific antigens on the majority of tumors. To evade this problem, we developed a new tumor-specific approach in which bispecific antibodies exploit chimerism after allogeneic BMT by redirecting donor T cells against recipient-specific antigens on tumor cells. Two different leukemia relapse models were established using a T-cell lymphoma (ST-1) and a B-cell lymphoma (BCL1) to evaluate the efficiency of such a therapy. In these experiments, irradiated BALB/c (Thy-1.2+, I-Ad) mice were transplanted with C57BL/6 Thy-1.1 (I-Ab) BM cells under the protection of graft-versus-host disease-preventing monoclonal antibodies. Forty-five days after BMT, the chimeric mice were injected with either 2 x 10(4) recipient-type, Thy-1.2+, CD3- ST-1 cells or major histocompatability complex (MHC) class II+ (I-Ad)-BCL1 cells. Four days later, the mice were treated with 8 microg bsAb G2 (anti-CD3 x anti-Thy-1.2) or 10 microg (+10 microg, day 6) bsAb BiC (anti-CD3 x anti-I-Ad), respectively. These combinations guaranteed exclusive binding of the bsAbs target arms to tumor cells, leaving the surrounding, donor-type hematopoietic cells unbound. Compared with the parental antibodies, the bsAbs markedly reduced tumor mortality. Between 34% and 83% of mice survived in the bsAb groups compared with 0% of the control groups treated with parental antibodies, clearly documenting the benefit of the redirection principle. Furthermore, cytokine release (interleukin-6) after anti-CD3 antibody or bsAb treatment was decreased by administering a low-dose antibody preinjection. We have shown (1) that 6 weeks after BMT, when donor T-cell reconstitution is still in progress, T-cell-redirecting bsAb are clearly superior to parental antibodies in terms of tumor cell elimination; and (2) that the polymorphism of a common antigen such as Thy-1 or a clinically more relevant target antigen such as MHC class II can be used as an operational tumor-specific antigen after allogeneic BMT.
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PMID:Bispecific antibodies target operationally tumor-specific antigens in two leukemia relapse models. 897 58

Human immunodeficiency virus type 1 (HIV-1) infection is associated with severe psoriasis, B cell lymphoma, and Kaposi's sarcoma. A deregulated production of interleukin-6 (IL6) has been implicated in the pathogenesis of these diseases. The molecular mechanisms underlying the abnormal IL6 secretion of HIV-1-infected cells may include transactivation of the IL6 gene by HIV-1. Here we report the molecular mechanisms of Tat activity on the expression of the IL6 gene. By using 5' deletion mutants of pIL6Pr-CAT and using IL6:HIV-1-LTR hybrid constructs where discrete regions of the IL6 promoter replaced the TAR sequence in HIV-1 LTR, we identified a short sequence of the 5'-untranslated region of the IL6 mRNA that is required for Tat to trans-activate the IL6 promoter. This sequence acquires a stem-loop structure and includes a UCU sequence that binds to Tat and is necessary for full trans-activation. In addition, we provide the evidence that Tat can function by enhancing the CAAT enhancer-binding protein (C/EBP) DNA binding activity and is able to complex with in vitro translated C/EBPbeta, which is a major mediator of IL6 promoter function. By using the yeast two-hybrid system and immunoprecipitation, we observed that the interaction of Tat with C/EBP proteins also occurred in vivo. The data are consistent with the possibility that Tat may function on heterologous genes by interacting with RNA structures possibly present in a large number of cellular and viral genes. In addition, Tat may function by protein-protein interactions, leading to the generation of heterodimers with specific transcription factors.
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PMID:HIV-1 Tat induces the expression of the interleukin-6 (IL6) gene by binding to the IL6 leader RNA and by interacting with CAAT enhancer-binding protein beta (NF-IL6) transcription factors. 916 58

Primary effusion lymphoma (PEL) is a distinct clinicopathologic entity associated with Kaposi's sarcoma-associated herpes virus (KSHV). Several cytokines, including interleukin-6 (IL-6), basic fibroblast growth factor (bFGF), and platelet-derived growth factor (PDGF) may be important for survival of KS cells. However, little is known about the interaction of cytokines with KSHV-infected lymphocytes from PEL. Therefore, we investigated what cytokines were produced by KSHV-infected PEL cell lines (KS-1, BC-1, BC-2), what cytokine receptors were expressed by these cells, what response these cells had to selected cytokines, and what was the effect of IL-6 antisense phosphorothioated oligonucleotides. Reverse transcriptase-polymerase chain reaction (RT-PCR) and protein studies showed that these three cell lines produced IL-10, IL-6, and the receptors for IL-6. The granulocyte macrophage colony-stimulating factor (GM-CSF), IL-1beta, IL-8, IL-12, bFGF, PDGF, and c-kit transcripts were not detected in the cell lines. High levels (0.7 to 5 ng/mL/10(6) cells/48 hours) of IL-6 protein were consistently detected in supernatants of the cell lines by enzyme-linked immunosorbent assay (ELISA) tests. In clonogenic assays, interferon-alpha (IFN-alpha) and IFN-gamma suppressed the clonal growth of the PEL cells, but GM-CSF, IL-4, IL-6, IL-8, IL-10, and oncostatin M did not change it. We examined for several autocrine loops that have been suggested to occur in KS. Experiments using antisense oligonucleotides showed that the clonal growth of KS-1 and BC-1 was nearly 100% inhibited by IL-6 antisense oligonucleotides (10 micromol/L), but not at all by either oligonucleotides (</=10 micromol/L) to IL-6 sense, IL-6 scrambled, viral IL-6 (vIL-6) antisense, or IL-10 antisense. Furthermore, the IL-6 antisense oligonucleotides had no effect on two B-cell lymphoma cell lines, which were not infected with KSHV. Addition of IL-6 antibody did not inhibit clonal growth of any of the cell lines. Taken together, we have defined the cytokines and their receptors expressed on PEL cells and have found that these cells synthesized IL-6 and IL-6 receptors; interruption of this pathway by IL-6 antisense oligonucleotides specifically prevented the growth of these cells. These findings will offer potential new therapeutic strategies for PEL.
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PMID:Mechanisms of growth control of Kaposi's sarcoma-associated herpes virus-associated primary effusion lymphoma cells. 951 48

Sixty six patients with non-Hodgkin's lymphomas (NHL) were studied, interleukin-6 (IL-6) was revealed in the blood sera of 33 patients. IL-6 was revealed more frequently in patients with high-grade malignant (p < 0.05) than in those with low-grade malignancy. The largest group of IL-6 positive patients included NHL patients with diffuse large B-cell lymphoma and angioimmunoblastic lymphoma. The marked relationship was found between the serum IL-6 levels and the stage of disease: the serum IL-6 level was significantly lower in untreated patients with Stages II and III disease than in those with end-stage (IV) NHL. IL-6 significantly decreased upon remission, comparable with its level before the initiation of treatment. Analysing the association of prognosis of disease with the serum IL-6 showed that in the group of patients with good (The SNLG index < 2) and intermediate (2 < SNLG index < by 2.6) prognosis, the concentration of this cytokine was significantly lower than in those with poor prognosis (SNLG index > 2.6). There was a significant decrease of the total survival rates of NHL with serum IL-6 found. Therefore, IL-6 is a good prognostic marker in NHL and associated with the activity of a malignant process. Additionally, the increased serum IL-6 levels correlated with NK activities positively and with serum IL-4 levels negatively.
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PMID:[Diagnostic and prognostic value of interleukin-6 in malignant non-Hodgkin's lymphomas]. 984 10

Hypercalcaemia as the only manifestation of B-cell lymphoma is seen very rarely. Its pathophysiology is heterogenous and not well understood. We report a 73-year-old man who presented with severe hypercalcaemia before any signs of malignancy became evident. He was diagnosed with a B-cell lymphoma on bone marrow trephine biopsy. The hypercalcaemia was associated with high plasma concentrations of parathyroid-hormone-related protein, interleukin-6 and tumour necrosis factor. Our patient had markedly increased osteoclast and osteoblast activity as a result of synergistic effects between these factors, with consequent severe hypercalcaemia. This is the first reported example of such combined effects of these factors in humans.
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PMID:Severe hypercalcaemia in B-cell lymphoma: combined effects of PTH-rP, IL-6 and TNF. 1062 79

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

Interleukin-6 (IL-6) can be involved in several diseases including lymphoid malignancies. This cytokine binds to soluble IL-6 receptor (sIL-6R) circulating in blood, leading to signal transduction via gp130. Soluble IL-6R shows agonistic activity for IL-6, and the soluble form of gp130 (sgp130) an antagonistic effect against the complex IL-6/sIL-6R. Viscum album extract (Iscador) as an immunomodulator is used in the treatment of malignant disorders. In this study we investigated the effect of this treatment on the serum levels of IL-6, sIL-6R and sgp130 in B-cell lymphoma patients (n = 27), in comparison to healthy controls (n = 28). Twenty-one of 27 patients had been treated previously with chemo/radiotherapy. The patients were divided into two groups; those with short-term (investigated before and during treatment) or those with long-term Viscum album (VA) therapy (investigated during therapy). The serum levels of the three parameters were determined by ELISA. In patients having short-term treatment IL-6 values were similar to those of controls. During long-term therapy the values were significantly lower (P<0.05). The values of sIL-6R were elevated only in long-term treated patients (P<0.05), the values of sgp130 in both short-term (P<0.05) and in long-term treated patients (P=0.001). There is a significant correlation (P<0.05) between levels of sIL-6R and sgp130 in both therapy groups at 24 hours after injection. This indicates that the potent effect of sIL-6R on the biological activity of IL-6 could be inhibited by sgp130 as antagonist. Clinical data show that half of the patients (6/12) with long-term treatment had a continuous complete remission, whereas only 2/15 patients with short-term treatment had a complete remission.
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PMID:Measurements of IL-6, soluble IL-6 receptor and soluble gp130 in sera of B-cell lymphoma patients. Does viscum album treatment affect these parameters? 1204 87

Kaposi's sarcoma-associated herpesvirus, the viral agent of Kaposi's sarcoma, is associated with two lymphoproliferative disorders: primary effusion lymphoma and multicentric Castleman's disease. To identify other lymphoproliferative conditions linked with Kaposi's sarcoma-associated herpesvirus, we studied non-Hodgkin's lymphomas arising in individuals with AIDS-associated Kaposi's sarcoma. Formalin-fixed tissues from 24 such lymphomas were examined. As expected, two primary effusion lymphomas were Kaposi's sarcoma-associated herpesvirus-positive, with immunohistochemistry demonstrating the Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen in the nuclei of all neoplastic cells. Additionally, three of seven evaluable cases of the immunoblastic variant of diffuse large B-cell lymphoma (immunoblastic lymphoma) showed similar latency-associated nuclear antigen staining. These Kaposi's sarcoma-associated herpesvirus-positive immunoblastic lymphomas resembled primary effusion lymphoma histologically but were not known to involve body cavities (sites included lymph nodes, soft tissues of the neck, and spleen). Notably, 5-20% of the neoplastic cells in the Kaposi's sarcoma-associated herpesvirus-positive immunoblastic lymphomas also showed cytoplasmic staining for viral interleukin-6, a biologically active cytokine homologue found in primary effusion lymphoma. We conclude that Kaposi's sarcoma-associated herpesvirus is present in some immunoblastic lymphomas in persons with AIDS-associated Kaposi's sarcoma.
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PMID:Immunoblastic lymphoma in persons with AIDS-associated Kaposi's sarcoma: a role for Kaposi's sarcoma-associated herpesvirus. 1274 48


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