Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have suggested that interleukin-6 (IL-6) may mediate growth of multiple myeloma (MM) in either an autocrine or paracrine growth mechanism. However, those molecules which can trigger IL-6 secretion either by tumor cells or non-MM marrow cells are not well characterized. In the present study, we have examined the expression and functional significance of CD40 on MM and plasma cell leukemia (PCL) cells and derived cell lines, as well as long-term bone marrow stromal cells (BMSCs) and derived cell lines. CD40 was expressed on the majority of MM cells (> 90%) and BMSCs (> 70%). Triggering via CD40 using NIH3T3 CD40 ligand transfectant (CD40LT) cells increased (> 30%) cell surface CD80, CD18, CD11a, CD11b, and CD11c expression on MM cell lines. Culture with either fresh or paraformaldehyde fixed NIH3T3 CD40LT cells upregulates IL-6 secretion in MM cells and MM-derived cell lines, as well as normal and MM bone marrow mononuclear cells (BMMCs), BMSCs, and BMSC lines; this effect can be specifically blocked by anti-CD40 monoclonal antibody (MoAb). BMMCs and BMSCs from patients with MM secreted significantly more IL-6 than those from healthy donors (n = 3, P < .001); moreover, after stimulation using CD40L, IL-6 secretion was fourfold greater (n = 3, P < .001) from MM BMMCs and BMSCs than from normal BMMCs and BMSCs. Myeloma (CD38+CD45RA-) cells and non-MM (CD38+CD45RA+, CD38-CD45RA+, and CD38-CD45RA-) BMMCs were separated by dual fluorescence cell sorting. The latter secreted fourfold more IL-6 than the former (n = 2, P < .001). Increased IL-6 secretion (up to 28-fold) and proliferation (Stimulation index 10) by CD38+CD45RA-MM cells was triggered by culture with NIH3T3 CD40LT cells. Finally, anti-CD40MoAb partially (30%) blocked tumor cell to BMSC adhesion-induced IL-6 secretion. These studies support the view that CD40L may trigger IL-6 secretion by both MM cells and BMSCs and that IL-6-mediated autocrine and paracrine growth mechanisms may be possible in MM.
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PMID:CD40 ligand triggered interleukin-6 secretion in multiple myeloma. 753 94

During mammalian ontogenesis, the thymic "pure" endodermal epithelial anlage develops and differentiates into a complex cellular microenvironment. Beginning the 7-8th week of intrauterine development, thymic epithelial cells chemotactically regulate (induce) numerous waves of migration of stem cells into the thymus, including the CD34+, yolk sac-derived, committed hematopoietic stem cells. In vitro experiments have established that CD34+ CD38dim human thymocytes differentiate into T lymphocytes when co-cultured with mouse fetal thymic organs. Hematopoietic stem cells for myeloid and thymic stromal dendritic cells (DCs) are present within the minute population of CD34+ progenitors within the mammalian thymus. The common myeloid, DC, natural killer (NK) and T lymphocyte progenitors have also been identified within the CD34+ stem cell population in the human thymus. Interactions between the endocrine and immune systems have been reported in various regions of the mammalian body including the anterior pituitary (AP), the skin, and the central (thymus) and peripheral lymphatic system. The network of bone marrow derived DCs is a part of the reticuloendothelial system (RES) and DCs represent the cellular mediators of these regulatory endocrine-immune interactions. Folliculo-stellate cells (FSC) in the AP, Langerhans cells (LCs) in the skin and lymphatic system, "veiled" cells, lympho-dendritic and interdigitating cells (IDCs) in a number of tissues comprising the lymphatic system are the cell types of the DC meshwork of "professional" antigen presenting cells (APCs). Most of these cells express the immunocytochemical markers S-100, CD1. CD45, CD54, F418, MHC class I and II antigens, Fc and complement receptors. FSCs are non-hormone secreting cells which communicate directly with hormone producing cells, a form of neuro-endocrine-immune regulation. As a result, an attenuation of secretory responses follows stimulation of these cells. FSCs are also the cells in the AP producing interleukin-6 (IL-6), and they have also been identified as the interferon-gamma responsive elements. FSCs also express lymphatic DC markers, such as DC specific aminopeptidase, leucyl-beta-naphthylaminidase, non-specific esterase, MHC class I and II molecules and various other lymphatic immunological determinants [platelet derived growth factor-alpha chain (PDGF-alpha chain), CD13, CD14 and L25 antigen]. There is strong evidence that such DCs in the AP, and similar ones in the developing thymus and peripheral lymphatic tissue are the components of a powerful "professional" antigen presenting DC network. These APCs contain a specialized late endocytic compartment, MIIC (MHC class II-enriched compartment), that harbors newly synthesized MHC class II antigens en route to the cell membrane. The limiting membrane of MIIC can fuse directly with the cell membrane, resulting in release of newly secreted intracellular MHC class II antigen containing vesicles (exosomes). DCs possess the ability to present foreign peptides complexed with the MHC molecules expressed on their surfaces to naive and resting T cells. There are a number of "molecular couples" that influence DC and T lymphocyte interaction during antigen presentation: CD/1/CD18 integrins, intercellular adhesion molecules (ICAMs), lymphocyte function associated antigen 3 (LFA-3). CD40, CD80/B7-1, CD86/B7-2, and heat-stable antigen. The "molecular couples" are involved in adhesive or co-stimulatory regulations, mediating an effective binding of DCs to T lymphocytes and the stimulation of specific intercellular communications. DCs also provide all of the known co-stimulatory signals required for activation of unprimed T lymphocytes. It has been shown that DCs initiate several immune responses, such as the sensitization of MHC-restricted T lymphocytes, resistance to infections and neoplasms, rejection of organ transplants, and the formation of T-dependent antibodies. (ABSTRACT TRUNCATED)
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PMID:Dendritic type, accessory cells within the mammalian thymic microenvironment. Antigen presentation in the dendritic neuro-endocrine-immune cellular network. 929 3

The escape of malignant cells from the immune response against the tumor may result from a defective differentiation or function of professional antigen-presenting cells (APC), ie, dendritic cells (DC). To test this hypothesis, the effect of human renal cell carcinoma cell lines (RCC) on the development of DC from CD34(+) progenitors was investigated in vitro. RCC cell lines were found to release soluble factors that inhibit the differentiation of CD34(+) cells into DC and trigger their commitment towards monocytic cells (CD14(+)CD64(+)CD1a-CD86(-)CD80(-)HLA-D Rlow) with a potent phagocytic capacity but lacking APC function. RCC CM were found to act on the two distinct subpopulations emerging in the culture at day 6 ([CD14(+)CD1a-] and [CD14(-)CD1a+]) by inhibiting the differentiation into DC of [CD14(+)CD1a-] precursors and blocking the acquisition of APC function of the [CD14(-)CD1a+] derived DC. Interleukin-6 (IL-6) and macrophage colony-stimulating factor (M-CSF) were found to be responsible for this phenomenon: antibodies against IL-6 and M-CSF abrogated the inhibitory effects of RCC CM; and recombinant IL-6 and/or M-CSF inhibited the differentiation of DC similarly to RCC CM. The inhibition of DC differentiation by RCC CM was preceeded by an induction of M-CSF receptor (M-CSFR; CD115) and a loss of granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR; CD116) expression at the surface of CD34(+) cells, two phenomenon reversed by anti-IL-6/IL-6R and anti-M-CSF antibodies, respectively. Finally, a panel of tumor cell lines producing IL-6 and M-CSF induced similar effects. Taken together, the results suggest that the inhibition of DC development could represent a frequent mechanism by which tumor cells will escape immune recognition.
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PMID:Inhibition of the differentiation of dendritic cells from CD34(+) progenitors by tumor cells: role of interleukin-6 and macrophage colony-stimulating factor. 984 45

The phenotype of a subpopulation(s) of human monocytes which has been shown to proliferate in vitro in response to macrophage colony-stimulating factor (M-CSF or CSF-1) and granulocyte-macrophage CSF (GM-CSF) is as yet unknown. To identify this proliferating subpopulation(s) we demonstrated first that DNA synthesis was occurring under culture conditions suitable for flow cytometric evaluation. Flow cytometric analysis of surface antigen expression identified that after 5 days of culture the proliferating subpopulation of monocytes expressed CD14, CD13, CD33, CD11b, CD11c, CD87, HLA-DR, CD45RO, and did not express CD86, CD34, CD80, CD4, CD16, and CD56. In addition, these proliferating monocytes (representing approximately 5% of total monocytes) were shown to produce the proinflammatory cytokines interleukin-6 and tumor necrosis factor alpha in response to lipopolysaccharide stimulation. Further characterization and subsequent isolation of this subpopulation of monocytes may provide new and important information necessary to understand inflammatory diseases such as rheumatoid arthritis, where local proliferation at the site of inflammation may be a key factor contributing to the chronicity of the disease.
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PMID:Characterization of a CSF-induced proliferating subpopulation of human peripheral blood monocytes by surface marker expression and cytokine production. 1061 77

Bacterial DNA and synthetic CpG-oligodeoxynucleotides (ODNs) derived thereof have attracted attention because they activate cells of the immune system in a sequence-dependent manner. Here we investigated the potential of CpG-ODNs to cause proliferation, cytokine production, and regulation of surface molecules in human B-chronic lymphocytic leukemia (CLL) cells. CpG-ODN induced proliferation in both B-CLL cells and normal B cells; however, only B-CLL cells increased proliferative responses when CpG-ODN was added to co-cultures of CD40-ligand transfected mouse fibroblasts (CD40LF) and B cells. Production of interleukin-6 and tumor necrosis factor alpha was detectable at borderline levels, using CpG-ODN as the only stimulus. In contrast, when CpG-ODN was added to co-cultures of B cells and CD40LF, a strong increase in cytokine production occurred in B-CLL cells as well as in normal B cells. The surface molecules CD40, CD58, CD80, CD86, CD54, and MHC class I molecules were up-regulated in B-CLL cells, whereas CD95 expression was not influenced by CpG-ODN stimulation. The same pattern of surface molecule regulation was observed in normal B cells, but up-regulation of CD40 was significantly stronger in B-CLL cells. Costimulation with CpG-ODN and CD40LF resulted in further up-regulation of CD58, CD80, CD86, and MHC class I molecules. In contrast, CD95 expression induced by CD40-ligation was inhibited by CpG-ODN. CpG-ODN activated B-CLL cells acquired a strong stimulatory capacity toward T cells in allogeneic mixed lymphocyte reaction. This effect was completely inhibited by a combination of anti-CD80 and anti-CD86 monoclonal antibody. Taken together, these findings suggest the possible use of CpG-ODN for immunotherapeutic strategies in patients with B-CLL.
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PMID:Immunostimulatory CpG-oligonucleotides cause proliferation, cytokine production, and an immunogenic phenotype in chronic lymphocytic leukemia B cells. 1064 15

Recombinant adenovirus (rAd) infection is one of the most effective and frequently employed methods to transduce dendritic cells (DC). Contradictory results have been reported recently concerning the influence of rAd on the differentiation and activation of DC. In this report, we show that, as a result of rAd infection, mouse bone marrow-derived immature DC upregulate expression of major histocompatibility complex class I and II antigens, costimulatory molecules (CD40, CD80, and CD86), and the adhesion molecule CD54 (ICAM-1). rAd-transduced DC exhibited increased allostimulatory capacity and levels of interleukin-6 (IL-6), IL-12p40, IL-15, gamma interferon, and tumor necrosis factor alpha mRNAs, without effects on other immunoregulatory cytokine transcripts such as IL-10 or IL-12p35. These effects were not related to specific transgenic sequences or to rAd genome transcription. The rAd effect correlated with a rapid increase (1 h) in the NF-kappaB-DNA binding activity detected by electrophoretic mobility shift assays. rAd-induced DC maturation was blocked by the proteasome inhibitor Nalpha-p-tosyl-L-lysine chloromethyl ketone (TLCK) or by infection with rAd-IkappaB, an rAd-encoding the dominant-negative form of IkappaB. In vivo studies showed that after intravenous administration, rAds were rapidly entrapped in the spleen by marginal zone DC that mobilized to T-cell areas, a phenomenon suggesting that rAd also induced DC differentiation in vivo. These findings may explain the immunogenicity of rAd and the difficulties in inducing long-term antigen-specific T-cell hyporesponsiveness with rAd-transduced DC.
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PMID:Recombinant adenovirus induces maturation of dendritic cells via an NF-kappaB-dependent pathway. 1100 Feb 34

Murine dendritic cells (DCs) can be classified into at least 2 subsets, "myeloid-related" (CD11b(bright), CD8alpha(-)) and "lymphoid-related" (CD11b(dull), CD8alpha(+)), but the absolute relationship between the 2 remains unclear. Methods of generating DCs from bone marrow (BM) precursors in vitro typically employ granulocyte-macrophage colony-stimulating factor (GM-CSF) as the principal growth factor, and the resultant DCs exhibit a myeloidlike phenotype. Here we describe a flt3-ligand (FL)-dependent BM culture system that generated DCs with more diverse phenotypic characteristics. Murine BM cells cultured at high density in recombinant human FL for 9 days developed into small lymphoid-sized cells, most of which expressed CD11c, CD86, and major histocompatibility complex (MHC) class II. The CD11c(+) population could be divided into 2 populations on the basis of the level of expression of CD11b, which may represent the putative myeloid- and lymphoid-related subsets. The FL in vitro-derived DCs, when treated with interferon-alpha or lipopolysaccharide during the final 24 hours of culture, expressed an activated phenotype that included up-regulation of MHC class II, CD1d, CD8alpha, CD80, CD86, and CD40. The FL-derived DCs also exhibited potent antigen-processing and antigen-presenting capacity. Neutralizing anti-interleukin-6 (IL-6) antibody, but not anti-GM-CSF, significantly reduced the number of DCs generated in vitro with FL, suggesting that IL-6 has a role in the development of DCs from BM precursors. Stem cell factor, which exhibits some of the same bioactivities as FL, was unable to replace FL to promote DC development in vitro. This culture system will facilitate detailed analysis of murine DC development.
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PMID:Generation of murine dendritic cells from flt3-ligand-supplemented bone marrow cultures. 1104 81

Epstein-Barr virus (EBV) classically infects and transforms B lymphocytes in vitro, yielding lymphoblastoid cell lines (LCLs). In contrast to other herpesviruses, EBV is not described as an infectious agent for monocytes. However, recent papers described in vitro infection of monocytes leading to abortive or transient viral expression. In the present study, we report the characterization of E1, a monocytic cell line infected and transformed by EBV. This cell line was derived from an LCL by a drastic electroporation and selection of neomycin-resistant cells, unfavorable to B-cell outgrowth. E1 expressed surface molecules of monocytic lineage (CD14, major histocompatibility complex class II, and CD80) and the c-fms gene, a highly specific marker for the monocytic lineage. This cell line is able to phagocytose and secrete proinflammatory monokines tumor necrosis factor alpha, interleukin-6 (IL-6), and IL-8. E1 cells are tumorigenic after injection in nude mice, and a monocytic cell line obtained from one of these tumors (TE1) displayed immunophenotype and functional properties similar to those of E1. We detected the presence of the EBV genome in both cell lines, as well as expression of the EBNA-1 and LMP-1, but not EBNA-2, viral genes, characteristic of a type II latency. LMP-1 influences the phenotype of these monocytic cell lines, as demonstrated by down-regulation of cell proliferation and membrane intercellular adhesion molecule 1 expression due to an LMP-1 antisense strategy. This is the first description of a latently infected human monocytic cell line and the first direct demonstration of an instrumental role for LMP-1 in the proliferation of EBV-transformed cell lines expressing a type II latency.
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PMID:Human monocytic cell lines transformed in vitro by Epstein-Barr virus display a type II latency and LMP-1-dependent proliferation. 1205 Mar 58

We studied concentration, phenotype, and function of peripheral blood (PB) dendritic cells (DCs) from patients with multiple myeloma (MM). The absolute number of circulating precursors of myeloid and plasmacytoid DCs was significantly lower in MM patients than in healthy subjects. After maturation, PBDCs from MM patients showed significantly lower expression of HLA-DR, CD40, and CD80 antigens and impaired induction of allogeneic T-cell proliferation compared with controls. Remarkably, they were not capable of presenting the patient-specific tumor idiotype to autologous T cells. Conversely, DCs generated in vitro from CD14(+) monocytes from the same patients, and PBDCs freshly isolated from healthy donors efficiently stimulated allogeneic and autologous T cells. To clarify the mechanism of PBDC deficiency in MM, we investigated the effects of the main plasma cell growth factor, interleukin-6 (IL-6), on the development of DCs from CD34(+) cells. IL-6 inhibited the colony growth of CD34(+) DC progenitors and switched the commitment of CD34(+) cells from DCs to CD14(+) CD1a(-) CD86(-)CD80(-) CD40(+/-)HLA-DR +/- monocytic cells exerting potent phagocytic activity but no antigen-presentation capacity. This effect was reversed by anti-IL-6 antibodies. Growing CD34(+) cells in the presence of autologous serum (without IL-6) also suppressed the development of functional DCs. This study demonstrates that PBDCs from MM patients are functionally defective, partially because of IL-6-mediated inhibition of development. This brings into question the advisability of using PBDCs as antigen carriers for immunotherapy trials in MM. The results also suggest a novel mechanism whereby myeloma cells escape immune recognition.
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PMID:Dendritic cells are functionally defective in multiple myeloma: the role of interleukin-6. 1207 32

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


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