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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To explore the mechanisms involved in the pathogenesis of human multiple myeloma (MM), we investigated the potential role of interleukin-6 (IL-6), a B-cell differentiation factor in humans, and a growth factor for rat/mouse heterohybridomas and murine plasmacytomas. Using a heterohybridoma assay, we found that two well-documented human myeloma cell lines, RPMI 8226 and U266, did not secrete IL-6 and did not express RNA messengers for IL-6. Neutralizing antibodies to IL-6 did not inhibit their proliferation, and recombinant IL-6 did not stimulate it. Taken together, these data show that IL-6 is not the autocrine growth factor of these human myeloma cell lines. A high production of IL-6 was found in the bone marrows of patients with fulminating MM, compared with patients with inactive or slightly active MM, or to healthy donors. This IL-6 production was assigned to adherent cells of the bone-marrow environment but not to myeloma cells. A spontaneous proliferation of myeloma cells freshly isolated from patients was observed in short-term cultures. Recombinant IL-6 was able to amplify it two- to threefold. The spontaneous proliferation of the myeloma cells was inhibited by anti-IL-6 antibodies and reinduced by recombinant IL-6. After 2 to 3 weeks of culture, the myeloma-cell proliferation progressively declined and no IL-6-dependent myeloma cell lines could be obtained despite repeated additions of fresh IL-6 and costimulation with other cytokines such as tumor necrosis factor (TNF)beta, or IL-1 beta. These data demonstrated a paracrine but not autocrine regulation of the growth and differentiation of myeloma cells by IL-6.
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PMID:Paracrine rather than autocrine regulation of myeloma-cell growth and differentiation by interleukin-6. 278 61

Human myeloma cells were purified from bone marrow aspirates from four patients having advanced myeloma, including one with common acute lymphoblastic leukemia antigen-positive myeloma. All of these myelomas had marked bone lytic lesions. From the culture supernatants of these purified myeloma cells, bone-resorbing activities were significantly revealed by 45Ca-release bone resorption assay, and IL-1 activities were also detected by IL-1 bioassay (mouse thymocyte comitogenic assay). Sandwich enzyme immunoassay for IL-1 alpha or IL-1 beta revealed that IL-1 beta was responsible for IL-1 activity of these culture supernatants. Furthermore, the bone resorbing activities of these culture supernatants were completely neutralized by pretreatment of anti-IL-1 beta, but not anti-IL-1 alpha antibody. By Northern blot analysis, IL-1 beta mRNA was identified from these myeloma cells. Therefore, it is concluded that myeloma cells produce IL-1 beta, which acts as bone-resorbing activity in multiple myeloma.
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PMID:Interleukin-1 beta rather than lymphotoxin as the major bone resorbing activity in human multiple myeloma. 278 13

Supernatants of freshly isolated human myeloma cell cultures were examined both for bone-resorbing activity (BRA) in vitro using newborn mouse calvaria, and for identification of the causal substances of the BRA. Eight of 14 culture supernatants of myeloma cells had BRA. All of these BRA-positive supernatants were from patients with marked destructive bone lesions of multiple myeloma. The presence of interleukin 1 (IL-1), especially IL-1 beta, was demonstrated in seven of these BRA-positive supernatants but not in BRA-negative supernatants. The concentrations of IL-1 beta were high enough to induce bone resorption in the newborn mouse calvaria assay and the BRA was totally abolished by pretreatment of the supernatants with anti-IL-1 beta antibody but not with either anti-IL-1 alpha antibody or normal serum. Other bone resorbing cytokines such as tumor necrosis factor or lymphotoxin were not present in high enough concentrations to stimulate bone resorption and their levels did not correlate with the BRA. IL-1 beta mRNA was also identified in BRA-positive myeloma cells. These results demonstrate that IL-1 beta is the principal agent of BRA present in supernatants of myeloma cell cultures, and also identify a possible role of IL-1 beta in destructive bone lesions in patients with multiple myeloma.
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PMID:Production of interleukin 1 beta, a potent bone resorbing cytokine, by cultured human myeloma cells. 278 4

In the present study the gene expression of cytokines promoting in vitro myeloma-cell growth was investigated by Northern blot analysis using total RNA of 36 tumour samples of patients with multiple myeloma (MM) or plasma cell leukaemia and poly(A)+ RNA of 10 human myeloma cell lines (HMCL). These cytokines included interleukin (IL)-1 alpha, IL-1 beta, IL-3, IL-6, granulocyte-macrophage (GM)-colony-stimulating factor (CSF) and granulocyte (G)-CSF. IL-1 beta, IL-6 and G-CSF genes were coexpressed in most patients, although at variable levels. IL-1 alpha transcripts were detected in 32% of patients in whom coexpression of IL-1 beta gene was found. IL-3 gene was not expressed in patients' cells and GM-CSF mRNA was detected in only 1/32 patients. No detectable transcripts for the above cytokines were present in HMCL, whereas IL-6 gene was expressed in 2/10 HMCL. We also looked for the presence of transcripts for IL-2, leukaemia inhibitory factor (LIF) and transforming growth factor (TGF)beta in cells of tumour samples from the same patients and in HMCL. IL-2 gene was not expressed in MM patients and HMCL. Weak expression of LIF gene was detected in three patients (9%), and transforming growth factor beta (TGF beta) mRNA was observed in 12/12 tumour samples analysed and all HMCL. These results suggest that, among cytokines shown to control myeloma-cell growth in vitro, IL-1, IL-6 and G-CSF could play a role in the development of myeloma disease in vivo.
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PMID:Cytokine gene expression in human multiple myeloma. 751 Sep 89

A number of environmental cells in the bone marrow (BM) of multiple myeloma (MM) has been reported to be activated. Evidence is growing that many cytokines, namely IL-6, IL-1 beta, TNF and GM-CSF, are detected in the BM of MM. Tumor environment may support, not only MM cell proliferation, but also bone resorption. In addition, immuno-regulatory cells, both CD8+T cells and NK cells, are also activated. High serum IL-2 levels are indicated. Recently, we detected numerous CD5+NK cells, which may be activated, in the peripheral blood and the BM of MM.
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PMID:[Myeloma cells and cytokines]. 769 93

Plasma cell malignancy, multiple myeloma, is the prototype of monoclonal terminal-differentiated B cell proliferation that reveals a monoclonal Ig in the serum and/or urine of the majority of patients. New insights into the biology and pathogenesis of this entity are based on careful research to a complex cytokine network including TNF beta, IL-1 beta, and IL-6, many oncogene products such as bc1-2 protein, H-ras p-21 protein, and RB-1 product, and cell surface antigens associated with myeloma cells. The recent understanding on the mechanism for acquisition of IgV region diversity during B cell development has clarified the origin of the clonogenic cell in multiple myeloma. Further identification of new prognostic parameters as well as new therapeutic agents is necessary for the rational therapy of this refractory malignancy.
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PMID:[Advances in biology and pathogenesis of multiple myeloma]. 769 96

Human myeloma cells have been supposed to produce osteoclast activating factors (OAF) that stimulate osteoclasts. The OAF from myeloma cell lines and freshly isolated myeloma cells has been attributed to TNF beta and IL-1 beta, respectively, although production of these cytokines is still controversial. Because of the bone resorption and latent renal dysfunction, hypercalcemia appears to develop readily in myeloma patients. The level of the cytokine production by myeloma cells appears to be relatively low; however, it may be sufficient to activate osteoclasts, because myeloma cells are present close to them. Recently, PTH-rP has been suggested to be involved in the bone resorption. In addition to conventional treatment of hypercalcemia, bisphosphonate may be a usefull tool to inhibit bone resorption.
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PMID:[Hypercalcemia in multiple myeloma]. 769 10

Multiple myeloma (MM) is a slow-growing malignancy whose plasma cells express the BCL-2 antiapoptosis gene. It is also associated with high levels of interleukin-6 (IL-6), a cytokine that prevents programmed cell death (PCD) in other target cell types. We thus investigated the ability of MM cells to undergo PCD and the possible regulatory effects of IL-6. Four MM cell lines underwent PCD when exposed to serum starvation, doxorubicin (dox), etoposide (VP-16), or dexamethasone (dex). Apoptosis was confirmed by morphologic criteria and/or detection of endonucleosomal DNA fragmentation. The concentrations of dox, VP-16, and dex required for PCD were at least 10-fold greater than that required to inhibit proliferation. Addition of IL-6 (but not IL-1 beta, IL-4, IL-7, or IL-10) inhibited PCD of 8226 targets induced by serum starvation or dexamethasone in a concentration-dependent fashion. In contrast, it had no effect on PCD induced by dox or VP-16. Exposure of targets to IL-6 did not increase BCL-2 expression (it actually consistently decreased expression), suggesting IL-6's protection against apoptosis was not mediated by direct effects on BCL-2. Targets protected from PCD by IL-6 were still sensitive to serum starvation and dex-induced cytostasis, but, after reculturing in drug-free complete media, they reinitiated normal proliferation. These data suggest that high levels of IL-6 may contribute to expansion of myeloma clones by inhibiting apoptotic death.
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PMID:Interleukin-6 inhibits apoptosis of malignant plasma cells. 774 52

Plasma cytokines and immune markers were assessed during the clinical management of 42 patients with multiple myeloma, MM. Of the patients 22/42 (all with progressive disease) were studied from the time of diagnosis, through various treatment regimes, to remission, progression or death. 5/42 patients had monoclonal gammopathy of undetermined significance (MGUS), 8/42 others had either indolent MM or stable MM, and a further 7/42 with progressive disease were also studied. IL-6, TNF-alpha, IL-1 alpha, IL-1 beta, beta 2 microglobulin (beta 2M), and neopterin were estimated in bloods taken under optimal conditions for cytokine detection. The levels were compared with a panel of samples from healthy volunteers. Both immunoreactive and biologically active plasma IL-6 levels were measured. Pretreatment IL-6 levels (both immunoreactive and biologically active) were found to correlate with severity of disease. In 13/22 patients with progressive disease who had been followed from the time of diagnosis over a 12-month period or until death, pretreatment IL-6 levels were predictive of response to therapy. Elevated plasma levels of TNF-alpha, beta 2M and neopterin were found in patients with progressive multiple myeloma, and this correlated with renal impairment. The analytes measured during the course of chemotherapy did not show correlation with disease progression or response to therapy.
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PMID:Multiple myeloma: an immunoclinical study of disease and response to treatment. 779 95

The authors review contemporary findings on the role of different components of the cytokine network from the aspect of development, prognosis and treatment of multiple myeloma. Greatest attention was devoted to the main growth factor of myeloma elements IL-6, but also to the real or so far sparsely elucidated role of other cytokines (IL-1, IL-2, GM-CSF, G-CSF, IL-3, IL-4, IL-5, IL-10, TNF, interferon alpha and gamma) under conditions in vitro and in vivo. For completeness sake the authors did not omit the problem of the soluble receptor of IL-2 and the role of TNF, TNF beta and in particular IL-1 beta in the pathogenesis of osteolytic lesions and the potential therapeutic role of antibodies against IL-6 (anti IL-6 mab) and interferon alpha and gamma.
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PMID:[The cytokine network in multiple myeloma]. 794 39


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