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)

An approach to obtain monoclonal antibodies directed against cell surface proteins induced by interferon has been developed in order to characterize such proteins and determine their role. Hybridomas obtained by fusion of murine myeloma cells and spleen cells of mice immunized with interferon-alpha-treated Daudi cells were screened for the production of antibodies reacting differentially with interferon-alpha-treated and untreated Daudi cells. One such hybridoma, 2D5, produced an antibody reacting with a 28/32 kDa homodimeric protein (p28/32) expressed at the surface of Daudi cells in response to IFN-alpha treatment. IFN-alpha treatment also increased the basal level of p28/32 detected on peripheral blood leukocytes (PBL). 2D5 Antibody was used to probe the expression of p28/32 on different cells and in response to various inducers. It appears that 2D5 reacted in fact with CD69, a marker of leukocyte activation and that, following IFN-alpha treatment, CD69 was not induced on all cultured cell lines tested. Interestingly, IFN-gamma was also able to induce CD69 expression on a restricted number of cell lines but the induction pattern only partially overlapped that of IFN-alpha. As expected, activation of cells with phorbol myristate acetate (PMA) resulted in a notable increase in the level of CD69 on all cell lines considered except for the epithelial and fibroblastic types.
Cytokine 1992 Jan
PMID:CD69 is expressed on Daudi cells in response to interferon-alpha. 161 56

Soluble forms of the interleukin (IL)-2, IL-4 and IL-7 receptors which lack the transmembrane domain have been described. IL-6 is a growth factor important in the final differentiation of B-cells into plasma cells and in the pathogenesis of multiple myeloma. To determine whether the receptor for IL-6 may exist as a soluble molecule, RNA was analysed from the transformed B-cell lines U266, CESS and Daudi, from bone marrow from two myeloma patients, and from normal leukocytes. Using polymerase chain reaction, oligonucleotide primers which flank the transmembrane domain were selected to generate a 339 bp fragment. All samples produced equivalent amounts of the expected 339 bp fragment plus a smaller 245 bp fragment except Daudi which exhibited virtual absence of both. Sequence analysis of the smaller fragments from each of the five samples demonstrated the deletion of the entire transmembrane region from codons 356 (G-TG) to 387 (AG-G). The boundaries of this deletion were identical in all cases. Partial sequence analysis of the ligand-binding domain for U266 demonstrated identical sequences for the membrane-bound and soluble forms of the IL-6 receptor cDNAs. In summary, an mRNA which encodes a soluble form of the IL-6 receptor is expressed in both normal and myeloma cells.
Cytokine 1992 Mar
PMID:Isolation of an mRNA encoding a soluble form of the human interleukin-6 receptor. 163 65

When bone-marrow cells from patients with multiple myeloma (MM) were seeded in short-term cultures, a spontaneous proliferation of the myeloma cells occurred for most of the patients with active disease and proliferating myeloma cells in vivo. In all cases, this spontaneous proliferation was inhibited by anti-IL-6 monoclonal antibodies (mabs). Moreover, myeloma cell lines, completely dependent upon exogenous IL-6 for their growth, could be reproducibly established by initially stimulating the myeloma cells with both IL-6 and GM-CSF. These results demonstrate that IL-6 is a major paracrine myeloma-cell growth factor in vitro. High serum IL-6 levels were observed in MM patients with active disease, especially patients with terminal disease. High IL-6 mRNA levels were found in bone-marrow cells of MM patients, mainly in myeloid and monocytic cells, in vivo. The myeloma cells did not express IL-6 mRNA. Injection of anti-IL-6 mabs to MM patients with terminal disease and extramedullary proliferation, completely blocked the myeloma-cell proliferation in vivo and completely inhibited the serum IL-6 bioactivity and the serum CRP levels. One patient with plasma cell leukemia and hypercalcemia was treated for two months with anti-IL-6 mabs and maintain in remission for 2 months without major side effects. Interestingly, the serum calcium levels also decreased in these patients. All these results show that IL-6 is the main cytokine responsible not only for the myeloma-cell proliferation in vivo, but presumably also for the large bone resorption processes observed in human MM.(ABSTRACT TRUNCATED AT 250 WORDS)
Eur Cytokine Netw
PMID:Interleukin-6 is the central tumor growth factor in vitro and in vivo in multiple myeloma. 210 41

Recombinant human transforming growth factor soluble receptor Type II (rhTGF-beta sRII) corresponding to the 159 amino acid extracellular domain of hTGF-beta RII has been expressed in insect cells using the baculovirus expression system or in a mouse myeloma cell line. N-terminal sequence analysis of the purified protein revealed the removal of the 23 amino acid signal peptide. In SDS-PAGE, the rhTGF-beta sRII resolves into multiple bands due to N-linked glycosylation. Recombinant hTGF-beta sRII is a TGF-beta antagonist and will inhibit the biological activities of TGF-beta 1, TGF-beta 3, and TGF-beta 5 on TGF-beta-responsive cell lines, such as murine HT-2 or human TF-1 with an ED50 of approximately 0.3 micrograms/mL. However, hTGF-beta sRII does not inhibit TGF-beta 2 bioactivities in these cell lines, suggesting that hTGF-beta RII has low affinity for TGF-beta 2. Polyclonal antibodies to hTGF-beta sRII have been produced in goats and purified on Protein-G affinity columns. This antibody can inhibit TGF-beta 1,2,3,5-dependent bioactivities on human cell lines such as TF-1. Additionally, this antibody has species cross-reactivity and will also inhibit TGF-beta-dependent bioactivities on murine cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Cytokine 1995 Jul
PMID:Characterization of recombinant soluble human transforming growth factor-beta receptor type II (rhTGF-beta sRII). 757 76

Mutagenesis of a region of human interleukin (IL)-6 which is important for triggering signal transduction via the IL-6 receptor beta-chain (gp130) has lead to the isolation of a variant of human IL-6 (IL-6.Q160E/T163P), which could antagonize the biological activity of wild type IL-6 on the human EBV transformed B cell line CESS and the human hepatoma cell line HepG2. Surprisingly this antagonistic IL-6 variant had an agonistic effect on the human myeloma cell line XG-1, albeit at a 1000-fold higher concentration than wild type IL-6. This residual activity of the mutant arose from triggering gp130, because it could be inhibited by a gp130 specific mAb. Extensive mutagenesis of residues between Q153 and H165 of human IL-6, a region which is partly homologous in cytokines which also signal via gp130 (oncostatin M, ciliary neurotrophic factor, leukaemia inhibitory factor, IL-11), did result in the isolation of a second antagonist for IL-6 activity on CESS and HepG2 cells. However on XG-1 cells this variant was active as well. These results suggest that (an) additional region(s) of the IL-6 molecule might be involved in gp130 triggering. Recently we indeed found that residues Lys42-Ala57 are also important for gp130 triggering. Inhibition experiments with neutralizing IL-6R alpha-chain specific mAb show that this region can be functionally separated from the Q153-H165 region. These findings have important implications for the development of receptor antagonists of IL-6 and IL-6 family members.
Cytokine 1995 Jul
PMID:Functional distinction of two regions of human interleukin 6 important for signal transduction via gp130. 757 77

We previously reported that injection of anti-IL-6 monoclonal antibody (mAb) in a patient with multiple myeloma (MM) induced the circulation of high amounts of IL-6 in the form of IL-6/anti-IL-6 monomeric complexes. This made it possible to estimate overall daily IL-6 production in patients in vivo, which had not been achieved in animals or humans before. In this study, estimations are given for a patient with MM who developed Escherichia coli sepsis during anti-IL-6 mAb. During the first 12 days, the overall IL-6 production was estimated at 1.5 to 2.0 micrograms/day. On day 13, serum IL-6 concentration, in the form of IL-6/anti-IL-6 complexes, increased 1000-fold and was 1.7 x 10(6) pg/ml, in relation with the development of E. coli sepsis. Overall IL-6 production was estimated to be greater than 7 mg/day, i.e. 3500 times higher than before sepsis. Serum IL-6 levels in the form of monomeric immune complexes remained very high for 20 days after sepsis indicating the persistence of very high overall IL-6 production (100 to 3500-fold greater than pre-sepsis production). This study demonstrates a considerable and persistent potential for IL-6 production in this patient during and after sepsis.
Cytokine 1993 Nov
PMID:Overall interleukin-6 production exceeds 7 mg/day in multiple myeloma complicated by sepsis. 818 69

Nano- to picomolar concentrations of high affinity IgG antibody to interleukin 6 (IL-6ab) were detected in sera of 71 of 467 normal Danish blood donors (15%). IL-6 bound to the Fab fragments of IL-6ab, and the antibody specifically and competitively interfered with enzyme-linked immunosorbent assays for human IL-6. Only IL-6ab-positive sera interfered with these ELISAs. A statistically positive correlation was found between total IL-6 binding and specific IL-6 binding to serum (P < 0.0001), suggesting that IL-6ab dominates as IL-6 binding factors in normal human serum. The IL-6ab also inhibited binding of IL-6 to receptors on the human U-937 macrophage-like cell line, the human U-266 myeloma cell line and the mouse hybridoma cell line B13.29, clone B9 (B9 cells). IL-6-induced proliferation of the B9 cells was competitively inhibited by IL-6ab. We conclude that sera of normal individuals may contain appreciable levels of autoantibodies to IL-6. These IgG autoantibodies may be physiologically and pathophysiologically important because they are potent inhibitors of IL-6 in vitro.
Cytokine 1993 Jan
PMID:High-affinity IgG autoantibodies to IL-6 in sera of normal individuals are competitive inhibitors of IL-6 in vitro. 848 7

A panel of monoclonal antibodies against the soluble IL-6 receptor was used to search for linear epitopes by a Pepscan analysis. Two such epitopes were found and the corresponding peptides were synthesized chemically. The peptides were active to inhibit the IL-6 dependent growth of human multiple myeloma cell line and the effect of IL-6 on growth of murine hybridoma cells. The epitope-defined, antagonist peptides reduced the transduction of the IL-6 signal which activates binding of Stat transcription factors to specific enhancers, but did not affect IL-6 binding. These effects were not seen with several other peptides from the IL-6 receptor sequence. A computer three-dimensional model of the IL-6 receptor complex was built and indicates that the antagonist peptides define one of the two possible sites of interaction between the domain-II of the IL-6 receptor molecule and that of the gp130 molecule within the hexameric receptor assembly.
Eur Cytokine Netw
PMID:Epitope peptides from interleukin-6 receptor which inhibit the growth of human myeloma cells. 858 70

A subclone of the EoL-3 human eosinophilic leukemia cell line (EoL-3.12) was selected for its high inducibility of CD23 (low affinity IgE receptor/Fc epsilon RII) by IL-4. Maximum membrane CD23 expression was detected after 16 h of incubation with IL-4, then gradually returned to basal level after 48 h. Membrane expression of CD23 on EoL-3.12 cells was found to parallel their homotypic aggregation. Extending the time of incubation with IL-4 to 48 h or more resulted in a de-aggregation of cells of cells with a shedding of membrane CD23 and an increase of its soluble form, sCD23. The IL-4-induced aggregation of EoL-3.12 cells was inhibited with anti-CD23 antibody or human myeloma IgE protein, indicating that it was mediated through the engagement of CD23. EoL3.12 incubated with IL-4 displayed morphological changes associated with differentiation, such as an increased number of lobulated nuclei with prominent nucleoli, increased ratio of cytoplasm and distinct cytoplasmic processes. EoL-3.12 cells incubated with IL-4 also displayed an enhanced adherence to human umbilical vein endothelial cells (HUVEC), which was reverted when the IL-4 incubation time extended. Furthermore, the transendothelial migration of EoL-3.12 cells toward a chemokinetic gradient of soluble CD23 (sCD23; 29 kDa fragment) closely paralleled the density of membrane CD23 expressed on EoL-3.12 cells. Additionally, the engagement of CD23 led to the activation of the L-arginine-dependent pathway of nitric oxide (NO) production, as detected by the increase in intracytoplasmic cGMP concentration. The capacity of EoL-3.12 cells to form homotypic as well as heterotypic adhesion appears therefore to be regulated, at least in part, by the level of CD23 expression.
Eur Cytokine Netw
PMID:Involvement of CD23/Fc epsilon RII in the homotypic and heterotypic cytoadhesion of the human eosinophilic cell line Eol-3. 858 71

We used reverse transcription-polymerase chain reaction (RT-PCR) to clone a rat complementary DNA that encoded the PVG rat granulocyte-macrophage colony-stimulating factor (GM-CSF). PCR products were cloned into a eukaryotic expression vector and transfected into the mouse myeloma cell line Sp2/0-Ag14. Cell culture supernatants of two of these transfectants supported proliferation of the growth factor-dependent cell line, DA-3, and promoted myeloid colony formation in rat and mouse bone marrow cell (BMC) cultures. The GM-CSF activity in these supernatants was neutralized by a polyclonal antibody to mouse GM-CSF. The cloning and expression of rat GM-CSF provides a valuable reagent for the study of the biology and clinical applications of the GM-CSFs.
J Interferon Cytokine Res 1995 Dec
PMID:Polymerase chain reaction cloning and expression of the rat granulocyte-macrophage colony-stimulating factor. 874 92


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