Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three interleukins with distinct functions, IL-4, IL-5 and IL-6, are involved in the regulation of B cell response into antibody producing cells. The studies with recombinant interleukins, however, demonstrated that the activities of these interleukins were not restricted to B lineage cells but showed a wide variety of biological functions on various tissues and cells. One of the most typical example of multifunctional interleukins is IL-6. It acts not only on B cells as B cell differentiation factor but also on T cells, hematopoietic stem cells, hepatocytes, nerve cells and myeloma cells. Deregulation of the expression of these interleukins was shown to be responsible for various diseases, such as i) IL-4 vs. immediate type hypersensitivity and ii) IL-6 vs. autoimmunity and multiple myelomas.
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PMID:Current concepts of B cell modulation. 869 Oct 54

It is known that anti-alpha(1 --> 3) dextran antibodies of BALB/c mice are ordinarily of distinctive idiotypes (Id), one of which is the individual idiotype (IdI) that is represented by J558 or M104E to myeloma protein. In the present study, we established T cell line of Th1 type which recognized the Id of anti-alpha(1 --> 3) dextran antibody, and investigated its specificity and functions. The T cell line, named J-2R, had a phenotype of CD3+ CD4+ CD8- and expressed alphabeta-T cell receptors (TcR). J-2R proliferated in response to J558 in an I-Ed-restricted manner but did not respond to M104E which had substitution at amino acids 100 and 101. We confirmed that J-2R recognized J558 IdI, using synthetic peptides corresponding to two serial amino acid residues, Arg100 and Tyr101, spanning the J558 IdI in the third hypervariable region (hv3) of the heavy chain. alpha(1 --> 3) dextran-binding B cells which were isolated from dextran-immunized mice activated J-2R, but B cells from nonimmune mice did not. J-2R produced IL-2, IFN-gamma and IL-6, but did not produce IL-4, IL-5, or IL-10. Furthermore, J-2R inhibited the growth of J558 myeloma cells inoculated to the syngeneic mice in vivo. These findings suggest that Id-specific CD4+ T cells, J-2R, are involved in Id network and may play a role in vivo. J-2R is useful for analysis of the role of the Id-specific helper T cells in immune network because J558 IdI is frequently present on anti-alpha(1 --> 3) dextran antibodies.
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PMID:Establishment and characterization of an anti-idiotypic CD4+ CD8- T cell line to murine anti-alpha(1 --> 3) dextran antibody. 895 18

Increased numbers of eosinophilic granulocytes that exhibit an activated phenotype are found in bronchial tissue and bronchial alveolar lavage fluid of patients with allergic asthma. Little is known about the processes that lead to activation of eosinophils in vivo, but Igs might be important stimulants. In the present study we investigated the capacity of human eosinophils to interact with beads coated with human serum IgG or IgA. Binding of IgG/IgA-coated beads to eosinophils from normal donors appeared to be dependent on priming with Th2-derived cytokines. Priming with granulocyte-macrophage CSF, IL-4, or IL-5 is required for eosinophils to form rosettes with IgA-beads. IL-4 priming resulted in a fast and transient effect on binding of IgA-beads, whereas the effect of IL-5 priming was slower and longer lasting. The expression of Fc alphaR (CD89) was low compared with that on neutrophils, and experiments with the blocking mAb My43 (CD89) showed no inhibition of rosette formation between eosinophils and IgA-coated beads. However, polymeric myeloma IgA effectively inhibited the rosette formation of IgA-coated beads to eosinophils. Binding of IgG-beads could only be primed with granulocyte-macrophage CSF and IL-5, not with IL-4. These data are concurrent with the hypothesis that Th2-derived cytokines spatially produced at the side of an allergic inflammatory response can direct eosinophils to a rather restricted primed phenotype by IL-4 or to a more generalized primed phenotype by IL-5.
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PMID:Differential effects of the T helper cell type 2-derived cytokines IL-4 and IL-5 on ligand binding to IgG and IgA receptors expressed by human eosinophils. 923 44

Evidence suggests that cellular adhesion is critical for eosinophil effector functions. Here, we tested the hypothesis that an adhesion molecule, specifically beta2 integrin, participates in intracellular signaling events of eosinophils. Eosinophils stimulated with interleukin (IL)-5 and adherent to protein-coated tissue culture plates via beta2 integrin (CD18) showed tyrosine phosphorylation of a number of proteins. Among these proteins, tyrosine phosphorylation of the 105 kD and 115 kD proteins and the product of the c-cbl protooncogene, Cbl, was specifically inhibited using soluble anti-CD18 monoclonal antibody (mAb) to block eosinophil cell adhesion. Furthermore, phosphoinositide turnover of IL-5-stimulated adherent eosinophils was also inhibited by anti-CD18 mAb, suggesting that cellular adhesion plays important roles in eosinophil signal transduction. alphaM beta2 (Mac-1, CD11b/18) was one of the beta2 integrins involved in eosinophil adhesion to protein-coated plates. We found that direct ligation of eosinophil alphaM beta2 with anti-CD11b mAb coupled to polystyrene microbeads induced tyrosine phosphorylation of a 115 kD protein and Cbl. Furthermore, anti-CD11b mAb microbeads induced increases in both phosphoinositide hydrolysis and the eosinophil degranulation response. Control antibodies, such as mouse myeloma IgG1 and anti-HLA class I antigen mAb, did not induce these cellular responses. These results suggest that engagement of beta2 integrin either by cell adhesion or by anti-CD11b mAb triggers activation of an intracellular signaling cascade, including protein tyrosine phosphorylation and phosphoinositide turnover, and subsequent cellular degranulation in human eosinophils. Tyrosine phosphorylation of a 115 kD protein and Cbl may play important roles in adhesion-dependent cellular functions of eosinophils.
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PMID:Ligation of the beta2 integrin triggers activation and degranulation of human eosinophils. 956 38

Using in situ hybridization and the reverse transcriptase polymerase chain reaction (RT-PCR) we show that messenger RNA for IL-4, IL-5 and tumor necrosis factor-alpha (TNF-alpha) is induced by cross-linkage of high-affinity Fc(epsilon) receptors (Fc(epsilon)RI) on human skin mast cells, but that only TNF-alpha mRNA is selectively induced by substance P. Skin mast cells were purified using the Percoll density technique. T cells were removed by serial negative selection using a CD2 monoclonal antibody (mAb) to achieve a final mast cell purity >95%. Purified mast cells were precultured with recombinant human stem cell factor (rhSCF; 10 ng/ml) and myeloma IgE (3 microg/ml) for 16 h before challenge with sheep polyclonal antihuman IgE antibody (anti-IgE; 1 or 10 microg/ml) in the presence of rhSCF (50 ng/ml). Using in situ hybridization, we demonstrated that IgE-dependent stimulation induces the expression of IL-4, IL-5 and TNF-alpha mRNA in skin mast cells. We have investigated the expression of IL-4, IL-5 and TNF-alpha mRNA by substance P, with the result that substance P, 0.003-30 microM, selectively induced TNF-alpha mRNA. However, substance P did not induce IL-4 mRNA and did not enhance IL-5 mRNA. Furthermore, we confirmed the release of TNF-alpha by substance P from skin mast cells using an ELISA technique. These findings demonstrate the capacity of human skin mast cells to transcribe IL-4, IL-5 and TNF-alpha by immunological activation and to transcribe and release TNF-alpha by substance P.
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PMID:Human skin mast cells produce TNF-alpha by substance P. 975 97

To investigate whether superantigen (SAG) from endogenous mouse mammary tumor virus functions as an immunogenic or a tumorigenic factor in tumor development, the BALB/c myeloma cell line FO was transfected with the SAG gene from the 3' Mtv-50 long terminal repeat (LTR) open reading frame (ORF), the product of which was specific for Vbeta6. All five transfectants expressing Mtv-50 LTR ORF mRNA showed stimulatory activity for Vbeta6 T-cell hybridomas in vitro; this activity was inhibited by the addition of anti-Mtv-7 monoclonal antibody (MAb) or anti-major histocompatibility complex class II I-A(d) and I-E(d) MAb. All transfectants with the SAG gene grew more rapidly than did mock transfectants in BALB/c mice after subcutaneous inoculation, whereas all clones, including mock transfectants, grew equally well in athymic nude mice. A significant fraction of Vbeta6 T cells selectively expressed activation markers, including CD44(high), CD62L(low), and CD69(high), and produced large amounts of interleukin 5 (IL-5) and IL-6 in BALB/c mice inoculated with transfectants. These results suggested that the expression of viral SAG enhances the tumorigenicity of a myeloma cell line through the stimulation of SAG-reactive T cells.
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PMID:Expression of mouse mammary tumor virus superantigen accelerates tumorigenicity of myeloma cells. 1095 19

To develop a model of early human adult B lymphopoiesis, we cultured CD34+CD38+CD10+ pro-B cells in contact with AFT024 stroma in X-VIVO10 media with 5% serum. The cytokines FLT3L + SCF + IL7 + IGF1 were added at day 0, IL4 + IL5 + IL6 + IL10 and soluble CD40 ligand at day 14, and Staph. aureus Cowan particles on day 21. Greater than 25-fold expansion of CD34+CD38+CD10+ cells was seen at 2 weeks, the majority being CD34-CD19+ pre-B cells. Differentiation to immature IgM+ B cells was seen at 3 weeks and mature IgD+ B cells at 4 weeks, with secretion of IgM into the media. Immature and mature B cells could also be generated from culture of CD34+CD10+CD19- and CD34+CD10+CD19+ cells under similar conditions. In conclusion, we have demonstrated in vitro differentiation of early pro-B cells, and possibly common lymphoid progenitor cells, to mature B cells. Additional stimuli, provided by T helper cells or dendritic cells for example, may be required for the generation of IgG+ B cells or plasma cells. However, our culture system should be a valuable tool to further investigate B cell biology and B cell malignancies such as multiple myeloma and lymphoma.
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PMID:A novel in vitro model of early human adult B lymphopoiesis that allows proliferation of pro-B cells and differentiation to mature B lymphocytes. 1099 8

Human interleukin (IL)-5 gene transcription is regulated by several transcription factor binding sites, including CLE 0, GATA, and a region from position -123 to -92 known as response element (RE)-II. By expression cloning, a partial protein was identified that bound to concatamers of RE-II. Recombinant protein derived from this initial complementary DNA (cDNA) encoding the partial protein specifically bound to RE-II-containing oligonucleotides in electromobility shift assays. The complete sequence (3,649 bp) was determined by 5' rapid amplification of cDNA ends and comparisons to existing ESTs, and found to be identical to the 3' half of Wolf-Hirschhorn syndrome candidate 1, (WHSC1; also known as Multiple Myeloma SET domain [MMSET]). The full-length protein contains an SET domain and two plant homeodomain-type zinc fingers. Transcription initiation of RE-II binding protein (RE-IIBP) messenger RNA (mRNA) uniquely occurred within the middle of WHSC1 near a region that exhibits complex mRNA splicing. RE-IIBP reactive polyclonal antisera identified proteins in human T-cell nuclear protein extracts of 62 and 66 kD that were consistent with the length of the longest open reading frame in RE-IIBP. In contrast, WHSC1 is predicted to encode a protein of 136 kD. In activated human Jurkat and murine D10.G4.1 T cells, expression of full-length and truncated forms of RE-IIBP repressed RE-II promoter activity of a 5X-RE-II luciferase reporter construct by as much as 75%. In addition, RE-IIBP expressed in activated D10.G4.1 T cells inhibited endogenous murine IL-5 production. The repressor activity of RE-IIBP is consistent with the presence of an SET domain that is found in other proteins that act as gene silencers.
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PMID:A unique mRNA initiated within a middle intron of WHSC1/MMSET encodes a DNA binding protein that suppresses human IL-5 transcription. 1115 55

The coexistence of multiple myeloma (MM) and mycosis fungoides (MF), and hence of both B- and T-cell neoplastic clones, is a rare event. We describe a case of plaque-stage MF associated with IgG lambda MM. The clinical onset of MF preceded that of MM, supporting the hypothesis that MF predisposed to the development of the B-cell proliferative disorder. The skin tumor cells were found to originate from CD4(+) T-lymphocytes, characterized by a V beta 8 receptor and no proviral human T-lymphotropic virus (HTLV)-I monoclonal integration. They also displayed a polarized Th1-type cytokine profile containing mRNAs for interleukin (IL)-2, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-beta, but not for IL-4, IL-5, or IL-10. The CD8(+)/CD57(+) suppressor-cytotoxic subpopulation was significantly increased in the peripheral blood and was associated with MM progression. Expression of p16INK4A, a gene from the INK family that inhibits cyclin-dependent kinases and regulates the cell cycle, was lacking in MF cells and bone marrow (BM) plasma cells. The p16INK4A gene was silenced by hypermethylation, suggesting that it plays a role in the early phase of the pathogenesis of both diseases. Thus, a lymphoid precursor cell presumably contains aberrations that induce the development of both clonal diseases in a multistep process.
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PMID:Multiple myeloma and mycosis fungoides in the same patient: clinical, immunologic, and molecular studies. 1210 63

CC-4047 (Actimid) and CC-5013 (Revimid) belong to a class of thalidomide analogs collectively known as the immunomodulatory drugs (IMiDs), which are currently being assessed in the treatment of patients with multiple myeloma and other cancers. IMiDs potently enhance T cell and natural killer cell responses and inhibit tumor necrosis factor-alpha, interleukin (IL)-1 beta, and IL-12 production from LPS-stimulated peripheral blood mononuclear cells. However, the molecular mechanism of action for these compounds is unknown. Herein, we report on the ability of the IMiDs to up-regulate production of IL-2 from activated human CD4+ and CD8+ peripheral blood T cells, production of IL-2 and IFN-gamma from T helper (Th)1-type cells, and production of IL-5 and IL-10 from Th2-type cells. Elevation of IL-2 production from Jurkat T cells was observed as early as 6 h poststimulation and correlated with an increase in IL-2 promoter activity that was dependent upon the proximal but not the distal AP-1 binding site. The IMiDs enhanced AP-1-driven transcriptional activity 2- to 4-fold after 6 h of T cell stimulation, and their relative potencies for AP-1 activation correlated with their potencies for increased IL-2 production in Jurkat T cells and in CD4+ or CD8+ human peripheral blood T cells. The most potent of these IMiDs, CC-4047, had no effect on nuclear factor of activated T cells transcriptional activity, calcium signaling, or phosphorylation of extracellular signal-regulated kinase 1/2, c-Jun NH2-terminal kinase 1/2, p38 mitogen-activated protein kinase, or c-Jun/Jun D in Jurkat T cells. These data suggest that IMiDs increase T cell cytokine production by potentiating AP-1 transcriptional activity.
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PMID:Enhancement of cytokine production and AP-1 transcriptional activity in T cells by thalidomide-related immunomodulatory drugs. 1264 1


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