Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0079731 (B-cell lymphoma)
 16,671 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Interleukin-6 (IL-6) plays a central role in the pathogenesis of several autoimmune and inflammatory diseases as well as B-cell lymphoproliferative disorders. This work describes the effects of the recombinant or adenovirally-delivered IL-6 superantagonist Sant7, anti-IL-6 and IL-6 receptor monoclonal antibodies in a severe murine model of human B-cell lymphoma induced in SCID mice by transplantation of an LCL-41 cell line variant (isotype-switched IgM>IgG). Survival of 60% of the animals treated with anti-gp130 was observed up to day 33, while about 20% of the animals survived with anti-gp80 and Sant7 treatment. No survival was observed with the anti-IL-6 monoclonal antibody treatment. No significant change in serum and peritoneal levels of human IL-6 (hIL-6) and soluble human IL-6 receptor (shIL-6R) was observed in the recombinant Sant7-treated group towards the control group. The anti-gp80 monoclonal antibody induced significant increase of both hIL-6R and hIL-6 in serum and peritoneum. The anti-gp130 monoclonal antibody treatment determined a reduction of the seric shIL-6R and a significant increase of the seric hIL-6. Anti-IL-6 monoclonal antibody administration resulted in a reduction of serum and in an increase of peritoneal hIL-6. Treatment with adenoviral Sant7 was associated with a reduction of circulating shIL-6R, hIgG and mSAP. However, only marginal anti-tumor efficacy of the adenoviral Sant7 was observed. Overall, the present data suggest a potential for anti-hIL-6 therapy in B-cell lymphomas. Less severe animal models might be useful to better evaluate Sant7 efficacy alone or in combination with other anti-IL-6 therapeutics.
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PMID:Comparative activity of Sant7 and anti-IL-6, IL-6R monoclonal antibodies in a murine model of B-cell lymphoma. 1606 91

Interleukin-6 (IL-6) affects the survival and proliferation of myeloma cells via autocrine and/or paracrine mechanisms. In this study, we investigated the effects of IL-6, IL-6 receptor antagonist (IL-6RA), and gp130 antagonist (gp130A) on the membrane expressions of IL-6R and gp130, on the viability, on the proliferation, on the DNA synthesis, and on the cell cycle phases in several multiple myeloma (MM) cell lines and B cell lymphoma cell lines. Our results showed that (1) all five MM cell lines (OPM-2, RPMI-8226, U-266, KMS-12-BM, MOLP-8) expressed surface IL-6R and gp130, the B cell lymphomas (WSU-1, DOHH-2, U-698) expressed only gp130; (2) exogenous IL-6 markedly up-regulated the expression of membrane IL-6R (up to 186%) and down-regulated the gp130 receptor (down to 4%) in MM cell lines, the membrane expression of gp130 in B cell lymphomas was not altered; (3) IL-6 markedly increased the spontaneous proliferation (up to 151%) in all MM cell lines, that of B cell lymphomas was not affected; (4) IL-6 increased the DNA synthesis in the S cell cycle phase of MM cells and arrested the stage G2/M, IL-6 was ineffective in any cell cycle phase of B cell lymphoma; (5) IL-6RA inhibited the membrane IL-6R partially, the proliferation was decreased only slightly; and (6) although gp130A inhibited the membrane gp130 completely, the proliferation was decreased 81-78% in MM and B cell lymphoma cell lines. This means that gp130 is not absolutely necessary for the cellular signalling cascade via JAK/STAT and RAS/MAPK pathways involved in proliferation and viability. Our results give an indication in the therapy of MM: IL-6 antibody (IL-6A) alone or in combination with IL-6RA. The latter could be more effective. This kind of therapy is not recommended for B cell lymphoma, as these cells have no IL-6R.
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PMID:Multiple myeloma and B cell lymphoma. Investigation of IL-6, IL-6 receptor antagonist (IL-6RA), and GP130 antagonist (GP130A) using various parameters in an in vitro model. 1689 69

Mistletoe (Viscum album) extract (Iscador) is used either alone or in combination with chemotherapy or radiotherapy in the treatment of tumor patients. In this study the effects of Viscum album Quercus (VA Qu) extract (1000 ng lectin and 6 microg viscotoxin/ml) in various doses were investigated in an in vitro model with tumor cells: three multiple myeloma (MM) cell lines (OPM-2, RPMI-8226, U-266) and three B cell lymphoma cell lines (U-698, DOHH-2, WSU-1). None of the three B lymphoma cell lines and none of the three multiple myeloma cell lines produced interleukin (IL)-6 spontaneously or after treatment with VA Qu extract. All three multiple myeloma cell lines expressed surface IL-6R and gp130, the B cell lymphomas expressed only gp130. Viscum album/Qu extract markedly downregulated the membrane expression of IL-6R and gp130 in RPMI-8226 (down to 29% and 32%) and the expression of gp130 in WSU-1 (down to 22%). There was a marked reduction of viable cells of RPMI-8226 (down to 28%) and WSU-1 (down to 8 %) at 100 microg/10(6) cells /ml. There was a clear relationship between the inhibition of proliferation and viability: the percentage reductions of the viable cells at 48 and 72 h were similar to those of proliferation at 24 and 48 h, respectively. This means that firstly the proliferation of the tumor cell is inhibited and then afterwards these cells die by apoptosis or necrosis. The inhibitory effect of VA Qu on the proliferation can be termed cytostatic, on the survival cytocidal. VA Qu was more effective in cells having a high proliferation rate than in those with a low proliferation rate. The effective dose range lay between 25 and 100 microg/10(6) cells/ml (5-20 ng lectin/10(6) cells/ml) for all parameters.
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PMID:Cytostatic and cytocidal effects of mistletoe (Viscum album L.) quercus extract Iscador. 1692 28

IL-35 is a member of the IL-12 family of cytokines that is comprised of an IL-12 p35 subunit and an IL-12 p40-related protein subunit, EBV-induced gene 3 (EBI3). IL-35 functions through IL-35R and has a potent immune-suppressive activity. Although IL-35 was demonstrated to be produced by regulatory T cells, gene-expression analysis revealed that it is likely to have a wider distribution, including expression in cancer cells. In this study, we demonstrated that IL-35 is produced in human cancer tissues, such as large B cell lymphoma, nasopharyngeal carcinoma, and melanoma. To determine the roles of tumor-derived IL-35 in tumorigenesis and tumor immunity, we generated IL-35-producing plasmacytoma J558 and B16 melanoma cells and observed that the expression of IL-35 in cancer cells does not affect their growth and survival in vitro, but it stimulates tumorigenesis in both immune-competent and Rag1/2-deficient mice. Tumor-derived IL-35 increases CD11b(+)Gr1(+) myeloid cell accumulation in the tumor microenvironment and, thereby, promotes tumor angiogenesis. In immune-competent mice, spontaneous CTL responses to tumors are diminished. IL-35 does not directly inhibit tumor Ag-specific CD8(+) T cell activation, differentiation, and effector functions. However, IL-35-treated cancer cells had increased expression of gp130 and reduced sensitivity to CTL destruction. Thus, our study indicates novel functions for IL-35 in promoting tumor growth via the enhancement of myeloid cell accumulation, tumor angiogenesis, and suppression of tumor immunity.
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PMID:Tumor-derived IL-35 promotes tumor growth by enhancing myeloid cell accumulation and angiogenesis. 2334 34

Aberrant activity of the glycoprotein 130 130/JAK/STAT3 (gp130/JAK/STAT3) signaling axis is a recurrent event in inflammation and cancer. In particular, it is associated with a wide range of hematological malignancies, including multiple myeloma and leukemia. Novel targeted therapies have only been successful for some subtypes of these malignancies, underlining the need for developing robust mouse models to better dissect the role of this pathway in specific tumorigenic processes. Here, we investigated the role of selective gp130/JAK/STAT3 activation by generating a conditional mouse model. This model targeted constitutively active, cell-autonomous gp130 activity to B cells, as well as to the entire hematopoietic system. We found that regardless of the timing of activation in B cells, constitutively active gp130 signaling resulted in the formation specifically of mature B cell lymphomas and plasma cell disorders with full penetrance, only with different latencies, where infiltrating CD138+ cells were a dominant feature in every tumor. Furthermore, constitutively active gp130 signaling in all adult hematopoietic cells also led to the development specifically of largely mature, aggressive B cell cancers, again with a high penetrance of CD138+ tumors. Importantly, gp130 activity abrogated the differentiation block induced by a B cell-targeted Myc transgene and resulted in a complete penetrance of the gp130-associated, CD138+, mature B cell lymphoma phenotype. Thus, gp130 signaling selectively provides a strong growth and differentiation advantage for mature B cells and directs lymphomagenesis specifically toward terminally differentiated B cell cancers.
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PMID:Activated gp130 signaling selectively targets B cell differentiation to induce mature lymphoma and plasmacytoma. 3139 40