Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q06643 (non-Hodgkin's lymphoma)
 11,307 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mantle cell lymphoma (MCL) is a B cell non-Hodgkin's lymphoma, characterized by a poor response to therapy and short survival. To assess the proliferative capacity, we cultured MCL cells, using irradiated 3T6 mouse fibroblasts transfected with human CD40L ('CD40 system') in the presence of different cytokines. Proliferation was measured by 3H-thymidine incorporation and by CFSE fluorescence. Thirteen out of 16 MCL cases proliferated well in the CD40 system. In 10 cases a strong response upon further addition of IL-10 was seen, whereas IL-4 had an additional effect in only four cases. CFSE staining of cells before and after culture showed an increased number of cell divisions in the IL-10/CD40L stimulated cells. The MCL cells remained CD5+CD19+. Neither plasma cell differentiation nor isotype switching was seen. The light chain expression was strictly monoclonal. IL-1beta, IL-2, IL-6, G-CSF and GM-CSF did not stimulate MCL proliferation. IL-10 receptor expression correlated with the response to IL-10 in the culture system and the effect of added IL-10 could be blocked by antibodies directed against IL-10 and the IL-10 receptor. Autocrine IL-10 production by the MCL cells was detected in eight of 10 cases tested. IL-10 receptor blocking decreased proliferation when no exogenous IL-10 was used in four of seven cases tested. EBV assessed by EBER in situ hybridization was not detected in six cases tested. In conclusion, MCL can successfully be cultured upon CD40 stimulation if 3T6 CD40L+ cells are used. In this context IL-10 is a costimulatory factor. IL-10 receptor expression seems to correlate with response to CD40 crosslinking and IL-10. Autocrine IL-10 production might play a role in the proliferation of this lymphoma. This culture system may be useful to test new treatment strategies for this, thus far, therapy-resistant lymphoma.
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PMID:Mantle cell lymphoma proliferates upon IL-10 in the CD40 system. 1094 46

On antigen challenge, T-helper cells differentiate into two functionally distinct subsets, Th1 and Th2, characterized by the different effector cytokines that they secrete. Th1 cells produce interleukin (IL)-2, interferon-gamma (IFN-gamma) and lymphotoxin-beta, which mediate pro-inflammatory functions critical for the development of cell-mediated immune responses, whereas Th2 cells secrete cytokines such as IL-4, IL-5 and IL-10 that enhance humoral immunity. This process of T-helper cell differentiation is tightly regulated by cytokines. Here we report a new member of the type I cytokine receptor family, designated T-cell cytokine receptor (TCCR). When challenged in vivo with protein antigen, TCCR-deficient mice had impaired Th1 response as measured by IFN-gamma production. TCCR-deficient mice also had increased susceptibility to infection with an intracellular pathogen, Listeria monocytogenes. In addition, levels of antigen-specific immunoglobulin-gamma2a, which are dependent on Th1 cells, were markedly reduced in these mice. Our results demonstrate the existence of a new cytokine receptor involved in regulating the adaptive immune response and critical to the generation of a Th1 response.
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PMID:Development of Th1-type immune responses requires the type I cytokine receptor TCCR. 1105 72

Treatment of patients with non-Hodgkin's lymphoma (NHL) is frequently hampered by development of chemoresistance. Rituximab is a chimeric mouse antihuman CD20 antibody that offers an alternative; however, its mechanism of action is not clearly understood. Treatment of lymphoma cell lines with Rituximab sensitizes the cells to the cytotoxic and apoptotic effects of therapeutic drugs, e.g., cisplatin, fludarabine, vinblastine, and Adriamycin. This study investigated the mechanism(s) involved in the reversal of drug resistance by Rituximab therapy. NHL cells synthesize and secrete antiapoptotic cytokines implicated in drug resistance, including interleukin (IL)-6, IL-10, and tumor necrosis factor alpha. We hypothesized, therefore, that sensitization by Rituximab may be due in part to modification of cytokine production. In this study, examination of cytokine secretion by NHL 2F7 tumor cells revealed down-regulation of IL-10 by Rituximab treatment. Moreover, cytotoxicity assays using exogenous IL-10 and IL-10-neutralizing antibodies demonstrated that IL-10 serves as an antiapoptotic/protective factor in these tumor cells against cytotoxic drugs. Furthermore, expression in 2F7 cells of the protective factor, Bcl-2, was shown to be dependent on IL-10 levels and down-regulated by Rituximab. Other gene products such as Bax, Bcl-x, Bad, p53, c-myc, and latent membrane protein-1 (LMP) were not affected by Rituximab treatment. Drug sensitization, as well as down-regulation of both IL-10 and Bcl-2, was corroborated in experiments using the NHL cell line 10C9. The Ramos and Daudi NHL cell lines were not sensitizable, nor did their Bcl-2 or IL-10 levels change. These studies demonstrate that one mechanism by which Rituximab sensitizes NHL to chemotherapeutic drugs is mediated through down-regulation of antiapoptotic IL-10 autocrine/paracrine loops and Bcl-2. The clinical relevance of these findings is discussed.
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PMID:Inhibition of interleukin 10 by rituximab results in down-regulation of bcl-2 and sensitization of B-cell non-Hodgkin's lymphoma to apoptosis. 1129 68

Cytokines and chemokines govern leukocyte trafficking, thus regulating inflammatory responses. In this study, the anti-inflammatory effects of low dose 17 beta-estradiol were evaluated on chemokine, chemokine receptor, and cytokine expression in the spinal cords (SC) of BV8S2 transgenic female mice during acute and recovery phases of experimental autoimmune encephalomyelitis (EAE). In EAE protected mice, 17 beta-estradiol strongly inhibited mRNA expression of the chemokines RANTES, MIP-1 alpha, MIP-2, IP-10, and MCP-1, and of the chemokine receptors CCR1, CCR2 and CCR5 at both time points. Conversely, ovariectomy, which abrogated basal 17 beta-estradiol levels and increased the severity of EAE, enhanced the expression of MIP-1 alpha and MIP-2 that were over-expressed by inflammatory mononuclear cells in SC. 17 beta-estradiol inhibited expression of LT-beta, TNF-alpha, and IFN-gamma in SC, but had no effect on IL-4 or IL-10, indicating reduced inflammation but no deviation toward a Th2 response. Interestingly, elevated expression of CCR1 and CCR5 by lymph node cells was also inhibited in 17 beta-estradiol treated mice with EAE. Low doses of 17 beta-estradiol added in vitro to lymphocyte cultures had no direct effect on the activation of MBP-Ac1-11 specific T cells, and only at high doses diminished production of IFN-gamma, but not IL-12 or IL-10. These results suggest that the beneficial effects of 17 beta-estradiol are mediated in part by strong inhibition of recruited inflammatory cells, resulting in reduced production of inflammatory chemokines and cytokines in CNS, with modest effects on encephalitogenic T cells that seem to be relatively 17 beta-estradiol insensitive.
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PMID:17 beta-estradiol inhibits cytokine, chemokine, and chemokine receptor mRNA expression in the central nervous system of female mice with experimental autoimmune encephalomyelitis. 1155 Feb 21

Endogenous cytokines are aberrantly produced in many cancers, and serve as autocrine growth factors or indicators in immune response to the tumors. Hence, cytokine deregulation is likely to participate in the development or evolution of the malignant process. Over the last few years, endogenous cytokine levels have been correlated with phenotypic manifestations of cancer and with prognosis. For instance, serum IL-6 levels are elevated in both relapsed and newly-diagnosed Hodgkin's and non-Hodgkin's lymphoma, and these levels correlate with established prognostic features. Furthermore, in diffuse large cell lymphoma, serum IL-6 level is an independent prognostic variable for both complete remission and failure-free survival. Serum IL-10 levels are also elevated in lymphoid malignancies and predict outcome. In some cases, it may be that the balance between endogenous cytokine agonists and antagonists is disrupted. For instance, in chronic myelogenous leukemia, high cellular (leukocyte) levels of IL-1 beta and low levels of IL-1 receptor antagonist (IL-1RA) are seen in advanced disease and correlate with reduced survival. The molecular mechanisms underlying cytokine deregulation are now being investigated, with preliminary data suggesting heterogeneous genetic driving forces, including oncogene aberrations and viral infection.
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PMID:Cytokine deregulation in cancer. 1176 63

Although Fas (APO-1/CD95) is expressed ubiquitously and induces cell death, it is also known to mediate other responses such as inflammation and angiogenesis in vivo. Previously, we have reported that Fas ligation induces selective expression of chemokines (IL-8 and MCP-1) in human astroglioma cells in vitro. In this study, we investigated whether Fas ligation can induce expression of other cytokines. Expression of IL-1alpha, IL-1beta, IL-6, IL-10, IL-12, IFN-beta, IFN-gamma, LT-beta, TGF-beta, TNF-a and TNF-beta mRNA levels in CRT-MG human astroglioma cells upon Fas ligation was investigated using RNase protection assay (RPA). We found that IL-6 mRNA is selectively induced upon Fas ligation, and IL-6 mRNA and protein expression was further investigated using single probe RPA and ELISA. To investigate the in vivo expression of IL-6, human brain specimens were homogenized and ELISA was performed for IL-6 expression. Herein, we demonstrate that: (1) Among these cytokines, only IL-6 was induced upon Fas ligation in a dose- and time-dependent manner; (2) A selective p38 MAP kinase inhibitor, SB202190, and a MEK inhibitor, U0126, suppressed induction of IL-6 mRNA and protein expression by Fas ligation; and (3) Glioblastoma multiforme samples (n = 11) contain significantly higher levels of IL-6 compared to those of control brains (n = 5), which correlate with increased levels of Fas. These results suggest that the Fas-FasL system may play a role in the regulation of tumor growth and survival by inducing the pleiotropic cytokine IL-6.
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PMID:Fas engagement increases expression of interleukin-6 in human glioma cells. 1194 22

AT helper 1 (Th1) immune response is considered more effective than T helper 2 (Th2) for anti-tumor immunity, but either response could potentially stimulate tumor cell growth in lymphomas. Moreover, both IL-4 and IL-2/IL-12 are used in experimental treatment models for non-Hodgkin's lymphoma (NHL) despite their differing ability to elicit Th2 or Th1 responses, respectively. Here, we investigate which T helper cytokines (Th1 or Th2) predominate in B cell NHL tissue and determine whether cytokine expression correlates with tumor cell growth, cell death, and survival in a series of 44 NHL patients. Overall, we observed both Th1 and Th2 cytokine expression at the mRNA level, detecting high levels of IFN-gamma, IL6 and IL-10 expression in the majority of tumors. Transcripts for the IL-12 subunits p35 (38 of 38) and p 40 (23 of 38) were frequently detected in NHL tissue, and high p40 levels were common in patients with a good prognosis. Furthermore, high IL-4 levels correlated with greater survival duration (P < 0.0024) but nor overall survival. Cytokine expression of IL-2, IFNgamma and IL-4 was significantly reduced in the high grade tumor group. Interestingly, there was a strong correlation between high IL-4 levels and reduced levels of apoptosis (P < 0.006) or proliferation (P < 0.0001), which has also been reported in leukemic models. This has important implications for the success of IL-4 as a treatment for low and high grade tumors.
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PMID:Th1/Th2 cytokine expression and its relationship with tumor growth in B cell non-Hodgkin's lymphoma (NHL). 1215 1

We have previously reported that specific anti-tumour cytotoxic T cells (CTL) can be differentiated from tumour-infiltrating lymphocytes (TIL) in non-Hodgkin's lymphoma. We found that the combination of interleukin (IL)-1, IL-2 and IL-12 was very efficient for expansion of CD8+ T-cell receptor (TCR)alphabeta+ T cells and for development of their ability to specifically lyse tumour cells. In this study, we investigated whether anti-tumour T cells could be generated from the peripheral blood of patients using the culture protocol developed for TIL. Autologous T cells and tumour B cells from five patients were included in this study. It was found that polyclonal anti-tumour cytotoxic effector cells were generated when cultured in the presence of IL-1beta, IL-2 and IL-12. Interestingly, tumour cells were lysed by perforin/granzyme-mediated cytolysis and not by CD95-mediated apoptosis. By performing inhibition experiments, it was observed that both CD8+ and CD4+ T cells were responsible for the cytotoxic effect and that they were able to recognize malignant B cells by either a major histocompatibility complex (MHC)-restricted or MHC-non-restricted mechanism. Intriguingly, in addition to interferon-gamma and tumour necrosis factor-alpha, IL-10 was secreted continuously during culture. The source of patient T cells used for the generation of anti-tumour CTL should be based on the results obtained with peripheral blood lymphocytes and TIL.
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PMID:Differentiation of anti-tumour cytotoxic T lymphocytes from autologous peripheral blood lymphocytes in non-Hodgkin's lymphomas. 1240 81

Cytokines play important roles in the pathogenesis of lymphomas. The aim of this study was to determine the relations between serum levels of interleukin-2 (IL-2), IL-6, and IL-10 and parameters of International Prognostic Index (IPI). Serum levels of IL-2, IL-6, and IL-10 were measured using a sensitive enzyme-linked immunosorbent assay in the pretreatment frozen sera from 43 patients with non-Hodgkin's lymphoma. The patients we included in the study were divided into two groups, one with high risk and the other with low risk according to the IPI in regard to their ages, stages, performance status, extranodal involvements, and serum levels of lactate dehydrogenase. In the high-risk group, serum levels of IL-2 (0.852 +/- 0.268 ng/ml), IL-6 (0.461 +/- 0.206 ng/ml), and IL-10 (0.816 +/- 0.240 ng/ml) were found to be higher than serum levels of IL-2 (0.667 +/- 0.170 ng/ml), IL-6 (0.355 +/- 0.075 ng/ml), and IL-10 (0.643+0.177 ng/ml) in the low-risk group ( < 0.05). There was a correlation between the patients with high risk according to the IPI criteria and high levels of serum cytokines (IL-2, IL-6, IL-10). Knowledge of the serum levels of these cytokines in patients with newly diagnosed aggressive non-Hodgkin's lymphoma may help us to have some information about the possible prognosis, the activation of disease, and to decide on appropriate therapeutic approaches for individual patients.
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PMID:Correlation of serum IL-2, IL-6 and IL-10 levels with International Prognostic Index in patients with aggressive non-Hodgkin's lymphoma. 1247

Hematopoietic malignancies have been shown to depend on cytokine growth factor autocrine/paracrine loops for growth and differentiation. This results in the constitutive activation of cytokine-mediated transcription factors like signal transducer and activators of transcription (STAT) 3 in non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM). Recent evidence demonstrates that cytokines also contribute to a drug-resistant phenotype in many tumor cell types. We hypothesized that inhibitors of the STAT3 pathway would sensitize drug-resistant and endogenous cytokine-dependent NHL and MM tumor cells to the cytotoxic effects of chemotherapeutic drugs. We examined an AIDS-related NHL cell line, 2F7, known to be dependent on interleukin (IL)-10 for survival and an MM cell line, U266, known to be dependent on IL-6 for survival. IL-10 and IL-6 signal the cells through the activation of Janus kinase (JAK)1 and JAK2, respectively. Thus, we investigated the effect of two chemical STAT3 pathway inhibitors, namely, piceatannol (JAK1/STAT3 inhibitor) and tyrphostin AG490 (JAK2/STAT3 inhibitor), on the tumor cells for sensitization to therapeutic drugs. We demonstrate by phosphoprotein immunoblotting analysis and electrophoretic mobility shift analysis that piceatannol and AG490 inhibit the constitutive activity of STAT3 in 2F7 and U266, respectively. Furthermore, piceatannol and AG490 sensitize 2F7 and U266 cells, respectively, to apoptosis by a range of therapeutic drugs including cisplatin, fludarabine, Adriamycin, and vinblastine. The specificity of the inhibitors was corroborated in experiments showing that piceatannol had no effect on U266 and, likewise, AG490 has no effect on 2F7. The sensitization observed by these inhibitors correlated with the inhibition of Bcl-2 expression in 2F7 and Bcl-xL expression in U266. Altogether, these results demonstrate that STAT3 pathway inhibitors are a novel class of chemotherapeutic sensitizing agents capable of reversing the drug-resistant phenotype of cytokine-dependent tumor cells.
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PMID:Inhibition of constitutive STAT3 activity sensitizes resistant non-Hodgkin's lymphoma and multiple myeloma to chemotherapeutic drug-mediated apoptosis. 1253 84


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