UMLS:C0026764 - FACTA Search

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

Monocyte chemoattractant protein-1 (MCP-1) belongs to the newly recognized "chemokine" superfamily of activation-inducible cytokines. We report here that MCP-1 gene-transferred mouse myeloma cells modulate tumor necrosis in myeloma-bearing nude mice. We established an MCP-1-producing myeloma cell line (X63-MCP-1) by transfection with human MCP-1 cDNA as well as interleukin-8-producing X63 cells (X63 IL-8). Each cell line showed the same growth characteristics in vitro, and 1 x 10(7) cells per mouse were injected into the peritoneal cavity resulting in the formation of tumors. Hematologic studies, including peripheral white blood cell counts and differentiation, showed no differences among the groups. They formed tumors in the same manner, which we observed from weeks 2.5 to 9. MCP-1 mice showed more tumor necrosis and infiltration of the macrophages into the tissue surrounding the tumor. In situ hybridization, using a partial cDNA as a probe, showed that macrophages contained MCP-1 mRNA. Bone marrow cell colony-forming assay showed a greater number of both granulocyte and macrophage colonies in MCP-1 mouse femur than in those of controls or interleukin-8 mice. MCP-1 has no direct stimulatory activity on stem cells, but longer exposure to MCP-1 in vivo might stimulate both granulocyte and macrophage progenitors and recruitment of macrophages into tumors, and it might explain the antitumor activity of macrophages in tumor-bearing nude mice.
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PMID:Monocyte chemoattractant protein-1 stimulates tumor necrosis and recruitment of macrophages into tumors in tumor-bearing nude mice: increased granulocyte and macrophage progenitors in murine bone marrow. 763 82

We have investigated which of the cytokines that are relevant in the in vitro growth of multiple myeloma (MM) malignant plasma cells are actually produced in vivo by MM patients. To this end, we have measured the levels of IL-1 beta, IL-3, IL-4, IL-6, IL-7, IL-8 and tumour necrosis factor-alpha (TNF-alpha) both in sera and in the supernatant of bone marrow (BM) stromal cell cultures from patients with MM and monoclonal gammopathy of undetermined significance (MGUS). The significance of our findings is three-fold. First, IL-6 and IL-8 are produced by MM BM stromal cells, while IL-1 beta, TNF-alpha, IL-4 and IL-7 are not. Second, IL-3 is the only cytokine consistently raised in serum samples: we have also detected low levels of serum IL-6 in a minority of cases, usually in advanced stage of the disease. Third, MM BM stromal cells are active IL-6 and IL-8 producers, while both normal and MGUS BM stromal cells are low producers, thus suggesting that in the BM of MM a number of environmental cells, that would normally be quiescent, are instead activated and that, in MM, activated BM stromal cells play an active role in supporting the progressive expansion of the B cell clone.
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PMID:Cytokines involved in the progression of multiple myeloma. 846 62

Two hybridoma clones, I8-S2 and I 8-63, secreting anti- IL-8 antibodies were constructed from fusion of immunized spleen cells of BALB/c mice with either Sp 2/0 or 653 myeloma cells. They recognized different epitopes on IL-8 molecule. IL-8 could activate human granulocytes and induce the elevation of [Ca2+]i. Through flow cytometry analysis the two clones displayed different neutralizing effects on the cell activation function of IL-8. The neutralizing effect of clone I8-S2 was apparently higher than that of clone I8-63. It is suggested that the cell activation function of IL-8 is restricted to a certain epitope of IL-8 molecule.
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PMID:Flow cytometry analysis of the neutralization effect of anti-IL-8 McAbs on IL-8-activated human granulocytes. 857 8

POEMS syndrome is a plasma cell dyscrasia that presents with numerous complications, one of which is rarely pulmonary hypertension. Here we present a case of POEMS syndrome with pulmonary hypertension who improved with steroids and six rounds of plasmapheresis done over 1 month, and we document the baseline immune mediator status and the changes associated with the therapeutic intervention. Serum levels of soluble immune mediators such as interleukin (IL)-5, IL-8, IL-10, and eotaxin were normal at baseline and throughout therapy, whereas those of tumor necrosis factor (TNF)-alpha, soluble TNF-receptor type I (sTNF-RI), IL-6, interferon (IFN)-gamma, IL-2, and sIL-2R, which were abnormally high at baseline normalized with steroids and plasmapheresis. Serum levels of sIL-6R, which were abnormally low at baseline, increased to normal after therapy. The latter results pinpoint not only potential mediators of the systemic manifestations of POEMS syndrome with pulmonary hypertension but also relevant markers in patient follow-up. In this respect, IL-6 has been involved in the pathogenesis of multiple myeloma and Castleman's disease, and the interplay between abnormally high levels of IL-6 and abnormally low levels of its soluble receptor, deficiencies that corrected with therapy in this patient, appears to be particularly relevant to the pathogenic manifestations of POEMS syndrome with pulmonary hypertension. These findings are discussed in the context of our current knowledge of the pathogenesis of pulmonary hypertension and of potential new therapeutic modalities for POEMS syndrome with pulmonary hypertension.
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PMID:Soluble immune mediators in POEMS syndrome with pulmonary hypertension: case report and review of the literature. 1065 28

CD28 is the major costimulatory molecule on T cells. CD28 activation, in conjunction with T-cell receptor engagement, up-regulates transcription of several cytokines, including interleukin-2 (IL-2), through transcriptional activation of the RE/AP composite element. Although CD28 is not normally expressed on B cells or plasma cells, more than 90% of extramedullary myelomas (a late stage B-cell neoplasm) express CD28. The functional significance of this is unknown. The results of this study demonstrate that CD28 stimulates transcriptional activation of RE/AP-based reporters in B cells and myeloma cells. However, CD28 stimulation does not up-regulate IL-2 production in myeloma cell lines, demonstrating that the IL-2 promoter may not be a relevant RE/AP-containing target of CD28 in myelomas. Instead, an RE/AP composite element has been identified within the promoter of the IL-8 gene, a chemokine that promotes angiogenesis. Furthermore, stimulation of endogenous CD28 expressed by 3 myeloma cell lines increased IL-8 production. Therefore, the study demonstrates that CD28 is functional in myelomas to up-regulate transcription of endogenous genes, including IL-8. The proposal is made that aberrant expression of CD28 may play a role in the progression of multiple myeloma.
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PMID:Endogenous CD28 expressed on myeloma cells up-regulates interleukin-8 production: implications for multiple myeloma progression. 1141 79

The revival of thalidomide began shortly after the drug was withdrawn from the market because of its teratogenic properties. Therapeutic effects of thalidomide were found accidentally in leprosy patients with erythema nodosum leprosum (ENL). Subsequent research widened the understanding of the activity of thalidomide, and with improved methodology and the augmented background knowledge of immunology it was possible to interpret the properties of thalidomide more coherently. Effects on tumour necrosis factor-alpha (TNFalpha) release play an important role in the ability of thalidomide to affect the immune system. Alteration of synthesis and release of cytokines such as interleukin (IL)-1, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12 and interferon-gamma is involved in the complex mechanisms of thalidomide. Thalidomide targets leucocytes, endothelial cells and keratinocytes, affecting them in a different manner and at different cellular levels. Changes in the density of adhesion molecules alter leucocyte extravasation and the inflammatory response in the tissue involved. Several mechanisms for the teratogenic action of thalidomide are currently under review, but this mode of action of the drug still remains unclear and we review evidence-based hypotheses for the teratogenicity of thalidomide. Thalidomide shows significant clinical impact in several diseases such as ENL in lepromatous leprosy, chronic graft-versus-host disease, systemic lupus erythematosus, sarcoidosis, aphthous lesions in HIV infection, wasting syndrome in chronic illness, inflammatory bowel disease, multiple myeloma and some solid tumours. In 1998 the US Food and Drug Administration approved thalidomide exclusively for the treatment of ENL, and strict conditions were stipulated for its use in order to prevent teratogenic adverse effects. However, despite the promising findings of thalidomide at the molecular level, namely its anti-TNFalpha properties and its intercalation with DNA, and activity in clinical trials, there is still a great need for more intensive research.
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PMID:Theoretical basis for the activity of thalidomide. 1160 49

Chemokines are cytokines which induce chemotaxis on many cell types, thus regulating cell migration within inflammatory and allergic sites, and leucocyte homing. Also, they play a crucial role in inflammatory and tumor-associated angiogenesis, as well as in tumor progression. Chemokines are grouped into: 1) alpha or CXC; 2) beta or CC; 3) gamma or C; 4) delta or CX3C molecules. Each of them recognizes one or more cell surface receptors, named CXCR, CCR, XCR, CX3CR respectively, according to the corresponding subfamily. Many chemokines have been identified within tumor tissues, as a secretory product of tumor cells and/or inflammatory cells. The CXC chemokines (such as IL-8, IP10, Mig, SDF-1 alpha) or CC chemokines (such as MCP-1, MIP-1 alpha, eotaxin, RANTES) have been frequently harvested from tumor tissues or the biological fluids of patients. Some chemokines inhibit tumor growth and progression by activating immunocompetent cytolytic cells or inhibiting tumor-associated angiogenesis. In contrast, other chemokines induce tumor progression by interacting with the specific receptor expressed on the tumor cells and hence by activating chemotaxis and secretion of proteolytic enzymes, or by inducing angiogenesis and metastatic spreading. Sometimes neoplastic cells express chemokine receptors which are not expressed on their normal counterpart. Data from this lab show the CXCR3 expression by cells from lymphoproliferative diseases, such as multiple myeloma and lymphoma, and the stimulation of an invasive phenotype following interaction with specific chemokines.
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PMID:[Chemokines and tumors]. 1248 85

Two common features in human immunodeficiency virus infection and acquired immunodeficiency syndrome, rheumatoid arthritis, and hematologic malignancies including multiple myeloma are elevated serum levels of beta(2)-microglobulin (beta(2)M) and activation or inhibition of the immune system. We hypothesized that beta(2)M at high concentrations may have a negative impact on the immune system. In this study, we examined the effects of beta(2)M on monocyte-derived dendritic cells (MoDCs). The addition of beta(2)M (more than 10 microg/mL) to the cultures reduced cell yield, inhibited the up-regulation of surface expression of human histocompatibility leukocyte antigen (HLA)-ABC, CD1a, and CD80, diminished their ability to activate T cells, and compromised generation of the type-1 T-cell response induced in allogeneic mixed-lymphocyte reaction. Compared with control MoDCs, beta(2)M-treated cells produced more interleukin-6 (IL-6), IL-8, and IL-10. beta(2)M-treated cells expressed significantly fewer surface CD83, HLA-ABC, costimulatory molecules, and adhesion molecules and were less potent at stimulating allospecific T cells after an additional 48-hour culture in the presence of tumor necrosis factor-alpha and IL-1beta. During cell culture, beta(2)M down-regulated the expression of phosphorylated mitogen-activated protein (MAP) kinases, extracellular signal-related kinase (ERK), and mitogen-induced extracellular kinase (MEK), inhibited nuclear factor-kappaB (NF-kappaB), and activated signal transducer and activator of transcription-3 (STAT3) in treated cells, all of which are involved in cell differentiation and proliferation. Thus, our study demonstrates that beta(2)M at high concentrations retards the generation of MoDCs, which may involve down-regulation of major histocompatibility complex class I molecules, inactivation of Raf/MEK/ERK cascade and NF-kappaB, and activation of STAT3, and it merits further study to elucidate the underlying mechanisms.
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PMID:Beta 2-microglobulin as a negative regulator of the immune system: high concentrations of the protein inhibit in vitro generation of functional dendritic cells. 1253 97

Because many studies have focused on growth factors in multiple myeloma, the study of the cytokine network appears to be useful for this purpose. Interleukin-6 (IL-6) and IL-2 with their soluble receptors (IL-3, IL-4, IL-10, and IL-11) have been examined. Plasma cells may produce IL-6 by an autocrine mechanism whereas a paracrine mechanism is believed to be involved in the production of IL-6 by bone marrow stromal cells through an interaction between adhesion molecules present on myeloma plasma cells and their respective receptors that are present on bone marrow stromal cells. In addition, control over production of IL-6 may be exerted by other ILs such as IL-1beta and IL-10. Among target cells, the growth of normal and myeloma plasma cells is supported by IL-6, which also induces the differentiation of myeloma plasmablastic cells into mature plasma cells. This last action also is shared by IL-3, IL-4, and, most likely, IL-8. Evaluation of the serum level of IL-6, C reactive protein, soluble IL-6 receptor (sIL-6R), and soluble IL-2 receptor (sIL-2R), together with the activity exerted by IL-3 and IL-4 on some cellular subsets, may constitute an additional element in the differential diagnosis of borderline cases. However, the concomitant evaluation of all immunologic parameters could be more useful than the value of a single IL. Serum levels of IL-6, sIL-6R, sIL-2R, and the expression of membrane-bound IL-2 receptors, both on bone marrow plasma cells and on peripheral blood mononuclear cells, are correlated with disease activity and disease stage. In addition, IL-6 and sIL-6R serum levels are believed to be correlated with the duration of disease-free survival because a high serum level at the time of diagnosis is believed to be correlated with a short duration of survival. However, some laboratory parameters may express the same prognostic value as high beta(2) microglobulin and lactate dehydrogenase (LDH) serum levels together with a high plasma cell labeling index are correlated with disease activity. Furthermore, if the evaluation is performed at the time of diagnosis, high values of these parameters are correlated with a short disease-free survival. A correlation between laboratory parameters and the serum level of several cytokines was demonstrated. Hence, the real advantage of the prognostic evaluation of cytokines is reserved for patients who do not exhibit uniform results with regard to beta(2) microglobulin and LDH serum levels, or, better, for borderline cases. With regard to the differential diagnosis, all immunologic parameters should be evaluated concomitantly rather than separately to confer a real prognostic value to results. Furthermore, a particular relation was found between a high sIL-6R serum level and a poor response to chemotherapy, therefore suggesting the possibility of identifying in advance a subset of patients with a high risk of treatment failure, as has already been demonstrated in other hematologic malignancies.Finally, the majority of studies indicate that interferons are used mainly in the immunotherapy for multiple myeloma, whereas many clinical trials should still be required for the evaluation of the effectiveness of anti-I-L6 antibodies or antiidiotypic vaccines in reference to the eligible patients for these particular therapies.
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PMID:A review of the cytokine network in multiple myeloma: diagnostic, prognostic, and therapeutic implications. 1273 43

Resveratrol, trans-3,5,4'-trihydroxystilbene, was first isolated in 1940 as a constituent of the roots of white hellebore (Veratrum grandiflorum O. Loes), but has since been found in various plants, including grapes, berries and peanuts. Besides cardioprotective effects, resveratrol exhibits anticancer properties, as suggested by its ability to suppress proliferation of a wide variety of tumor cells, including lymphoid and myeloid cancers; multiple myeloma; cancers of the breast, prostate, stomach, colon, pancreas, and thyroid; melanoma; head and neck squamous cell carcinoma; ovarian carcinoma; and cervical carcinoma. The growth-inhibitory effects of resveratrol are mediated through cell-cycle arrest; upregulation of p21Cip1/WAF1, p53 and Bax; down-regulation of survivin, cyclin D1, cyclin E, Bcl-2, Bcl-xL and clAPs; and activation of caspases. Resveratrol has been shown to suppress the activation of several transcription factors, including NF-kappaB, AP-1 and Egr-1; to inhibit protein kinases including IkappaBalpha kinase, JNK, MAPK, Akt, PKC, PKD and casein kinase II; and to down-regulate products of genes such as COX-2, 5-LOX, VEGF, IL-1, IL-6, IL-8, AR and PSA. These activities account for the suppression of angiogenesis by this stilbene. Resveratrol also has been shown to potentiate the apoptotic effects of cytokines (e.g., TRAIL), chemotherapeutic agents and gamma-radiation. Phamacokinetic studies revealed that the target organs of resveratrol are liver and kidney, where it is concentrated after absorption and is mainly converted to a sulfated form and a glucuronide conjugate. In vivo, resveratrol blocks the multistep process of carcinogenesis at various stages: it blocks carcinogen activation by inhibiting aryl hydrocarbon-induced CYP1A1 expression and activity, and suppresses tumor initiation, promotion and progression. Besides chemopreventive effects, resveratrol appears to exhibit therapeutic effects against cancer. Limited data in humans have revealed that resveratrol is pharmacologically quite safe. Currently, structural analogues of resveratrol with improved bioavailability are being pursued as potential therapeutic agents for cancer.
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PMID:Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. 1551 85

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