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

Interleukin-9 (IL-9) is a Th2 cytokine whose overexpression is associated with asthma and T cell lymphomagenesis. All the IL-9 activities studied so far are mediated by a specific hemopoietin receptor that activates a Jak/STAT pathway. Searching for genes specifically modulated by IL-9, we observed that the 24P3 mRNA is strongly upregulated in BW5147 T lymphoma cells upon IL-9 stimulation. 24P3 is a member of the lipocalin family, and has been reported to bind N-formyl-Met-Leu-Phe, a potent neutrophil chemoattractant, and possibly other lipophilic mediators of inflammation. A similar 24P3 induction was observed in other T cell lymphomas (EL4 and TH201) in response to IL-9, as well as in EL4 cells stimulated with IL-6 or IL-1. By contrast, other IL-9-responsive cells such as mast cell line MC9 and B cell lymphoma A20 showed no 24P3 induction upon IL-9 stimulation. Experiments using IL-9R mutants indicated that STAT transcription factors, particularly STAT3, are involved in this process. However, 24P3 gene induction was slow, reaching a plateau from 36 to 72 hours after stimulation and was inhibited if cells were treated with cycloheximide during the first 8 hours of IL-9 stimulation, suggesting an indirect induction requiring new protein synthesis.
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PMID:Interleukin-9 induces 24P3 lipocalin gene expression in murine T cell lymphomas. 1128 60

In persons with human immunodeficiency virus (HIV) infection and/or acquired immunodeficiency syndrome (AIDS), the immune system becomes dysfunctional in many ways. There is both immunodeficiency due to the loss of CD4-positive T helper cells and hyperactivity as a result of B-cell activation. Likewise, both decreases and increases are seen in the production and/or activity of cytokines. Cytokine changes in HIV infection have been assessed by a variety of techniques, ranging from determination of cytokine gene expression at the mRNA level to secretion of cytokine proteins in vivo and in vitro. Changes in cytokine levels in HIV-infected persons can affect the function of the immune system, and have the potential to directly impact the course of HIV disease by enhancing or suppressing HIV replication. In particular, the balance between the pro-inflammatory cytokines interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha, which up-regulate HIV expression, and IL-10, which can act both as an anti-inflammatory cytokine and a B-cell stimulatory factor, may play an important role in the progression to AIDS. In light of its ability to suppress the production of pro-inflammatory cytokines and, under some conditions, suppress HIV replication, increased IL-10 may be viewed as beneficial in slowing HIV disease progression. However, an association between increased IL-10 and the development of AIDS-associated B-cell lymphoma highlights the bifunctional nature of IL-10 as both an anti-inflammatory and B-cell-stimulatory cytokine that could have beneficial and detrimental effects on the course of HIV infection and AIDS.
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PMID:Pro- and anti-inflammatory cytokines in human immunodeficiency virus infection and acquired immunodeficiency syndrome. 1224 99

IL-6 is a multifunctional cytokine involved in differentiation and proliferation of immune cells. Moreover, it has diverse effects on the proliferation of tumor cells in vivo and in vitro. Although stimulating cell growth of multiple myeloma cells, it inhibits the proliferation of B16 melanoma cells and lung cancer cells. B9.55 cells, B-cell lymphoma, are IL-6-dependent cells, definitely requiring exogenous IL-6 for growth. When the cDNA for IL-6 was transfected into B9.55 cells, they began growing in an autocrine pattern without exogenous IL-6. To investigate the effects of IL-6 on B9.55 lymphoma in vivo, IL-6-transfected B9.55 cells (B9.G7) or neotransfected B9.55 cells (B9.vec) were injected subcutaneously into syngeneic mice. Initially, B9.G7 outgrew B9.vec, but after 3 weeks, B9.G7 grew slower than B9.vec. In addition, 5 micro g of recombinant human IL-6 was injected daily into the tumor site. Reduced tumor sizes of IL-6-treated rats, similar to those observed in mice which received B9.G7, indicated that IL-6 itself is the mediator of tumor regression. When B9.G7 cells were injected into the irradiated normal mice, tumor regression was released compared with the untreated normal control, suggesting that radiosensitive host components were involved in the regression of B9.G7 cell growth. However, the tumor regression of B9.G7 cells was not released in SCID mice. Histologically, B9.G7 tumor demonstrated severe necrosis and apoptotic cells with infiltration of host inflammatory cells. Above data indicate that IL-6 functions as an autocrine growth factor for B9.G7 cells in vitro, but behaves as an autocrine inhibiting factor in vivo. These contrasting effects of IL-6 on tumor cells in vitro and in vivo will be facilitative in understanding the interaction of cytokines and host immune systems.
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PMID:IL-6 Undergoes Transition from in vitro Autocrine Growth Factor toin vivo Growth Inhibitor of B Lymphoma Cells. 1238 81

The B cell lymphoma (BCL)-6 transcriptional repressor protein is an important regulator of Th2 responses. Mice deficient in BCL-6 develop severe Th2-type inflammation that can develop even in the absence of IL-4 signaling. We have investigated the mechanism for how BCL-6 regulates Th2 cell differentiation and have found that IL-6 signaling can promote dramatically increased levels of Th2 differentiation in BCL-6(-/-) CD4 T cells compared with wild-type CD4 T cells. IL-6 can induce a low level of Th2 cytokine expression in BCL-6(-/-)STAT6(-/-) cells but not in STAT6(-/-) cells. Since the promoters for Th2 cytokines such as IL-4, IL-5, IL-10, and IL-13 do not contain consensus BCL-6 DNA binding sites, we investigated whether BCL-6 might regulate the GATA-3 transcription factor that activates the expression of multiple Th2 cytokines. Consistent with the idea that BCL-6 represses GATA-3 expression, we found that GATA-3 levels are up-regulated in BCL-6(-/-)STAT6(-/-) CD4 T cells compared with STAT6(-/-) CD4 T cells. Retrovirus-mediated expression of BCL-6 in BCL-6(-/-)STAT6(-/-) T cells as well as developing wild-type Th2 cells leads to a potent repression of IL-4 and IL-10 secretion. Retrovirus-mediated expression of BCL-6 in both BCL-6(-/-)STAT6(-/-) and wild-type T cells also leads to a significant decrease in GATA-3 protein levels. Surprisingly, BCL-6 does not appear to regulate GATA-3 mRNA levels and thus BCL-6 appears to regulate GATA-3 expression at a posttranscriptional level. Regulation of GATA-3 protein levels is likely a key mechanism for how BCL-6 regulates Th2 cytokine expression and Th2 differentiation independently of STAT6. These data also point to a novel regulatory mechanism for BCL-6 separate from transcriptional repression.
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PMID:Inhibition of Th2 differentiation and GATA-3 expression by BCL-6. 1259 67

Reticuloendotheliosis viral oncogene homolog/nuclear factor of kappa light polypeptide gene enhancer in B cells 1 (Rel/NF-kappaB) activation is a ubiquitous outcome of engaging Toll-like receptors (TLRs), yet the cell-type-specific functions of this pathway in response to particular microbial signals remain poorly defined. Here we show that NF-kappaB1 and C-Rel, Rel/NF-kappaB proteins induced in conventional dendritic cells (cDCs) and plasmacytoid dendritic cells (pDCs) by cytosine-phosphate-guanosine (CpG) DNA, a TLR-9 ligand, serve markedly different functions in these DC subsets. With the exception of impaired interleukin-12 (IL-12) production, cultured Nfkb1(-/-)C-Rel(-/-) cDCs responded relatively normally to CpG DNA. In contrast, CpG-treated Nfkb1(-/-)C-Rel(-/-) pDCs, which were still able to produce type I interferon and regulated on activation normal T-cell expressed and secreted (RANTES), but not IL-6 or IL-12, failed to acquire an activated dendritic phenotype and underwent apoptosis. Although the TLR-9-mediated death of Nfkb1(-/-)C-Rel(-/-) pDCs, which coincided with a failure to up-regulate the prosurvival proteins B-cell lymphoma apoptosis regulator xL (Bcl-x(L)) and A1, was blocked by Bcl-2 transgene expression, this inhibition of apoptosis still failed to rescue the differentiation defects. This indicated that these NF-kappaB transcription factors independently regulate TLR-9-mediated pDC morphogenesis and survival. Collectively, these findings establish that NF-kappaB1 and c-Rel, while largely dispensable for TLR-9-induced cDC activation, are critical for regulating differentiation and survival programs during pDC activation.
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PMID:Distinct roles for the NF-kappaB1 and c-Rel transcription factors in the differentiation and survival of plasmacytoid and conventional dendritic cells activated by TLR-9 signals. 1603 93

IL-6 is a growth and survival factor for myeloma cells, although the mechanism by which it induces myeloma cell proliferation through gene expression is largely unknown. Microarray analysis showed that some B-cell lymphoma-associated oncogenes such as Bcl6, which is absent in normal plasma cells, were upregulated by IL-6 in IL-6-dependent myeloma cell lines. We found that Bcl6 variant 2 was upregulated by STAT3. ChIP assay and EMSA showed that STAT3 bound to the upstream region of variant 2 DNA. Expression of p53, a direct target gene of Bcl6, was downregulated in the IL-6-stimulated cells, and this process was impaired by an HDAC inhibitor. Bcl6 was knocked down by introducing small hairpin RNA, resulting in decreased proliferation and increased sensitivity to a DNA damaging agent. Thus, STAT3-inducible Bcl6 variant 2 appears to generate an important IL-6 signal that supports proliferation and survival of IL-6-dependent myeloma cells.
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PMID:IL-6-induced Bcl6 variant 2 supports IL-6-dependent myeloma cell proliferation and survival through STAT3. 1618 30

Although rituximab is an effective and safe therapy for B-cell lymphoid malignancies, a few cases of severe infusion-related reactions have been reported. Severe refractory distributive shock is an infrequent side-effect of treatment with rituximab and, to our knowledge, there are no reports describing its pathogenesis in a case of fatal outcome in detail. We present for the first time a case of fatal rituximab infusion-related refractory distributive shock in a patient with CD5+ diffuse large B-cell lymphoma (DLBCL) and analyse the pathogenic mechanisms involved. We have compared measurements obtained from the patient that experienced lethal refractory shock with the four subsequent DLBCL patients treated with rituximab, either at diagnosis or upon relapse, at our center. Serum cytokines [interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70] and complement components C3 and C4 were analysed, both pretreatment, and 3 h and 9 h after the onset of infusion. When compared with the control subjects, the potential risk factors for rituximab toxicity displayed by the patient that suffered refractory shock included C4 hypercomplementemia, IFN-gamma and IL-10 hypercytokinemia, as well as a high tumor burden. The refractory shock was distributive with most cytokines (IFN-gamma, TNF-alpha, IL-2, IL-4, IL-6 and IL-8) peaking 3 h after infusion and coinciding with the onset of the shock. Furthermore, the concentrations of IL-10 were persistently elevated. In conclusion, the cytokine pattern was similar to that observed in patients with rapid onset septic shock and serum cytokines reached levels markedly higher than previously described in other cases of severe rituximab infusion-related toxicity.
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PMID:Pathogenic study of anti-CD20 infusion-related severe refractory shock in diffuse large B-cell lymphoma. 1632 34

The adaptor protein B cell lymphoma 10 (Bcl10) plays an essential role in the functions of the AgRs in T and B cells. In this study, we report that Bcl10 also plays an important role in mast cells. Bcl10 is expressed in mast cells. Although Bcl10-deficient mast cells undergo normal development, we demonstrate that Bcl10 is essential for specific functions of FcepsilonR. Although Bcl10-deficient mast cells have normal de novo synthesis and release of the lipid mediator arachidonic acid, the mutant cells possess impaired FcepsilonR-mediated degranulation, indicated by decreased serotonin release, and impaired cytokine production, measured by release of IL-6. In addition, Bcl10-deficient mice display impaired IgE-mediated passive cutaneous anaphylaxis. Moreover, although Bcl10-deficient mast cells have normal FcepsilonR-mediated Ca(2+) flux, activation of PI3K, and activation of the three types of MAPKs (ERKs, JNK, and p38), the mutant cells have markedly diminished FcepsilonR-mediated activation of NF-kappaB and decreased activation of AP-1. Thus, Bcl10 is essential for FcepsilonR-induced activation of AP-1, NF-kappaB, degranulation, and cytokine production in mast cells.
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PMID:B cell lymphoma 10 is essential for FcepsilonR-mediated degranulation and IL-6 production in mast cells. 1718 39

The activated B cell-like (ABC) subgroup of diffuse large B-cell lymphoma (DLBCL) is characterized by constitutive activation of the nuclear factor-kappaB (NF-kappaB) pathway. In this study, we showed that the NF-kappaB pathway induced the expression of the cytokines interleukin (IL)-6 and IL-10 in ABC DLBCL cell lines, which also have high levels of total and phosphorylated signal transducer and activator of transcription (STAT) 3 protein, suggesting autocrine signaling. Using RNA interference for STAT3, we defined a gene expression signature of IL-6 and IL-10 signaling through STAT3. Based on this signature, we constructed a molecular predictor of STAT3 signaling that defined a subset of ABC DLBCL tumors with high expression of STAT3, IL-6, and/or IL-10 and their downstream targets. Although the STAT3-high and STAT3-low subsets had equivalent expression of genes that distinguish ABC DLBCL from germinal center B cell-like DLBCL, STAT3-high ABC DLBCLs had higher expression of signatures that reflected NF-kappaB activity, proliferation, and glycolysis. A small-molecule inhibitor of Janus kinase signaling, which blocked STAT3 signature expression, was toxic only for ABC DLBCL lines and synergized with an inhibitor of NF-kappaB signaling. These findings suggest that the biological interplay between the STAT3 and NF-kappaB pathways may be exploited for the treatments of a subset of ABC DLBCLs.
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PMID:Cooperative signaling through the signal transducer and activator of transcription 3 and nuclear factor-{kappa}B pathways in subtypes of diffuse large B-cell lymphoma. 1816 Jun 65

Cytokines play important roles in the pathogenesis of lymphomas. This study aimed to determine the relationship(s) between serum levels of interleukin (IL)-6, IL-8 and IL-10, measured by enzyme-immunoassay, and the clinical characteristics and outcomes in 46 untreated patients with diffuse large B-cell lymphoma (DLBCL). Serum IL-6, IL-8 and IL-10 levels were higher in DLBCL patients than in control subjects. Elevated levels of IL-6, IL-8 and IL-10 correlated with more adverse disease features. Consequently, patients with elevated IL-6, IL-8 and IL-10 levels prior to treatment had a lower response to therapy. Furthermore, those with elevated IL-6 and IL-10 levels had poor median, 3-year and 5-year survival, while elevated serum IL-8 level did not correlate with overall survival. Worse survival was also confirmed in patients with combined elevated pretreatment serum levels of IL-6, IL-8 and IL-10 (none, one, two or three elevated). Multivariate analysis identified elevated values of IL-6 and IL-10 and response to therapy as significant predictors for overall survival. Serum levels of IL-6, IL-8 and IL-10 before treatment of patients with newly diagnosed DLBCL may give some insight into the possible prognosis and thus facilitate the decisions regarding therapeutic approaches for individual patients.
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PMID:Correlation of serum IL-6, IL-8 and IL-10 levels with clinicopathological features and prognosis in patients with diffuse large B-cell lymphoma. 1847 2


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