Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Primary effusion lymphoma (PEL) is a new lymphoma entity occurring predominantly, but not exclusively in HIV+ patients with acquired immunodeficiency syndrome (AIDS). PEL grows exclusively in body cavities as serous lymphomatous effusion without evidence of mass disease or dissemination. The cells are infected with the newly discovered human herpesvirus-8 (HHV-8), often accompanied by co-infection with Epstein-Barr virus (EBV). Several lymphoma cell lines have been established from patients with AIDS- and non-AIDS-associated PEL. Given their phenotypical relationship to plasma cells, several cytokines may be important for growth and survival of PEL cells. We investigated the spectrum of cytokines produced by nine HHV-8+ PEL cell lines, in comparison with five Burkitt lymphoma, seven other B non-Hodgkin's lymphoma (B-NHL) and seven multiple myeloma-derived cell lines. In addition, we tested the response of the PEL cells to selected cytokines and the effects of neutralizing anti-cytokine and anti-cytokine receptor antibodies. Using specific ELISAs, PEL cell lines were found to produce large amounts of interleukin-6 (IL-6; 10-5000 pg/ml), IL-6 soluble receptor (IL-6sR; 30-600 pg/ml), IL-10 (600-80,000 pg/ml) and oncostatin M (OSM; 50-80 pg/ml) which in most cases were significantly higher than the levels produced by the Burkitt, B-NHL or myeloma cell lines; on the contrary, PEL cell lines did not elaborate significant levels of macrophage inhibitory protein (MIP-1alpha) and leukemia inhibitory factor (LIF). However, the levels of MIP-1alpha were increased 10- to 100-fold by treatment with phorbol ester TPA. PEL cell lines did not respond proliferatively to IL-6, IL-10, IL-11, LIF, MIP-1alpha, or OSM. Incubation with IL-6sR and IL-6 inhibited cell growth. Anti-IL6 neutralizing antibodies had no effect on PEL cell line proliferation; conversely, whereas anti-IL6R alone inhibited only weakly, anti-gp130 and anti-gp130 plus anti-IL6R showed strong inhibitory effects (>20% inhibition in 5/9 lines and >60% inhibition in 3/9 lines). In summary, PEL cell lines produce high amounts of cytokines (IL-6, IL-10, OSM); proliferation could be inhibited by blocking the receptors of the IL-6 signaling pathway.
Leukemia 1999 Apr
PMID:Constitutive cytokine production by primary effusion (body cavity-based) lymphoma-derived cell lines. 1021 73

We investigated the serum concentration of interleukin-6 (IL-6) and four IL-6 family cytokines - oncostatin M (OSM), leukaemia inhibitory factor (LIF), interleukin-11 (IL-11) and ciliary neurotrophic factor (CNTF) as well as IL-6 soluble receptor (sIL-6R) - using an enzyme-linked immunosorbent assay (ELISA) in 67 patients with multiple myeloma (MM) and 24 healthy controls, for a possible association between the serum levels of these peptides with disease activity and known prognostic factors. sIL-6R was detectable in all 67 and IL-6 in 65 (97%) patients. Both peptides were measurable in all healthy controls. In contrast, OSM was detectable in 30 (44.8%) MM patients and in only four (16.6%) normal individuals. The serum levels of IL-6, OSM and sIL-6R were significantly higher in MM patients compared with control group (P < 0.001, P < 0.03 and P < 0. 001 respectively). The highest concentrations of these cytokines were found in patients with progressive disease and the lowest in MM patients with stable disease and in healthy persons. LIF was detectable in four (6%), CNTF in 28 (41.8%) and IL-11 in eight (11. 9%) of the patients with MM. In the control group LIF, CNTF and IL-11 were measurable in 8.3%, 33.3% and 8.3% respectively. The serum concentration of these cytokines did not correlate either with clinical stage or with the phase of disease and was similar to those in healthy individuals. We found significant positive correlation between IL-6 levels and OSM (P < 0.001). We also observed positive correlation between beta2-M concentration and serum levels of IL-6 (P < 0.002), sIL-6R (P < 0.02) and OSM (P < 0.04) as well as a positive relationship between CRP and IL-6 (P < 0.001) and OSM (P < 0.002). In conclusion, the serum levels of IL-6, OSM and sIL-6R, but not LIF, IL-11 and CNTF, may be useful markers of MM activity.
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PMID:Circulating IL-6-type cytokines and sIL-6R in patients with multiple myeloma. 1023 12

Leukaemia inhibitory factor (LIF) and interleukin (IL)-6 are members of a cytokine group that share a common signal transducer gp130 and induce pleiotropic biological effects in cells of diverse lineage. In monocytes, LIF facilitates differentiation, which may stimulate the biosynthesis of tissue factor (TF) that initiates the coagulation cascade. We tested the hypothesis that LIF would enhance TF expression in human monocyte-derived macrophages (MDMs). Human peripheral blood mononuclear cells separated from whole blood by density centrifugation were allowed to differentiate into MDMs in primary culture, and were then exposed to LIF, IL-6 and oncostatin M (OSM) for 24 h. LIF and IL-6 receptors, and gp130 were demonstrated in MDMs by immunocytochemistry and RT-PCR. TF procoagulant activity (TF-PCA) was measured by recalcification clotting time and TF protein by Western blotting. The results show that both TF procoagulant activity and TF protein increased significantly in response to LIF over the concentration range of 1-100 nM (P < 0.03). Although OSM and IL-6 tended to enhance TF expression by MDMs, the increase did not reach statistical significance. Anti-LIF receptor and anti-gp130 antibodies attenuated the effect of LIF on TF expression as assayed by both bioassay and flow-cytometry. In conclusion, LIF increases TF-PCA and TF protein in MDMs, and specific anti-LIF receptor antibodies attenuate this effect. Thus, LIF may regulate by a gp130-dependent pathway macrophage-mediated procoagulant function in diverse pathological states involving inflammation and thrombosis and seems to serve as an important mediator at the interface between these processes.
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PMID:Leukaemia inhibitory factor enhances tissue factor expression in human monocyte-derived macrophages: a gp130-mediated mechanism. 1060 79

We investigated both in vitro and ex vivo the role of mature osteoblasts (OB) and bone marrow stromal cells (BMSC) in RA and OA by analysing the expression of the following IL-6-type cytokines: IL-11, leukaemia inhibitory factor (LIF), oncostatin M (OSM) and IL-6. OB and BMSC were isolated from femora of RA, OA and post-traumatic (PT) patients, cultured in vitro in the presence or absence of IL-1beta and tumour necrosis factor-alpha (TNF-alpha), and assessed for the production and mRNA expression of IL-6-type cytokines. Trabecular bone biopsies were obtained from the inner portions of femoral heads and used for cytokine in situ immunostaining. Cultured OB and BMSC from different patients constitutively secreted IL-11 and IL-6 but not OSM. LIF was secreted only by BMSC, at very low levels. Interestingly, IL-11 basal production was significantly higher in BMSC than in OB in all three groups tested. IL-1beta and TNF-alpha strongly stimulated IL-6-type cytokine release (except for OSM) by both OB and BMSC. OSM was expressed only at mRNA levels in all groups studied. Cytokine immunostaining on bone biopsies confirmed the data obtained on cultured cells: IL-11, IL-6 and LIF proteins were detected both in mesenchymal (BMSC and OB) and mononuclear cells; OSM was found only in mononuclear cells. These data demonstrate that IL-6-type cytokines are constitutively expressed in the bone compartment in RA, OA and PT patients and can be secreted by bone cells at different stages of differentiation (BMSC and OB). This suggests that these cytokines may be involved in the mechanisms of bone remodelling in OA and RA.
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PMID:Osteoblasts and stromal cells isolated from femora in rheumatoid arthritis (RA) and osteoarthritis (OA) patients express IL-11, leukaemia inhibitory factor and oncostatin M. 1063 74

The role of oncostatin M in bone metabolism is not clearly defined, and the actions of mouse oncostatin M (mOSM) on osteoclast development has not been previously determined. We therefore examined the ability of recombinant mOSM to stimulate osteoclast formation and activity using cocultures of murine calvaria and bone marrow cells, and compared the responses to other members of the interleukin 6 family of cytokines including mouse leukaemia inhibitory factor (LIF), cardiotrophin-1 (CT-1) and IL-6. Mouse OSM, LIF and CT-1 strongly induced the formation of tartrate resistant acid phosphatase positive (TRAP(+)) multinucleated cells (MNC) in a dose-dependent fashion. OSM, LIF or CT-1 also elevated the number and size of resorptive pits when cocultures were added to smooth cortical bone slices, indicating enhancement of osteoclast activity. The activity of OSM was reduced by indomethacin (10(-8)-10(-6) M), whereas addition of dexamethasone (DEX) at 10(-7)-10(-5) M synergistically enhanced OSM-induced numbers of TRAP(+)MNC. DEX (10(-7) M) costimulation also synergistically enhanced TRAP(+)cell numbers of LIF, and CT-1 treated cocultures. IL-6 had no activity alone, but further enhanced TRAP(+)cell formation in mOSM or DEX (10(-7) M) treated cocultures. When added to mouse calvarial osteoblast cultures, mOSM induced secretion of IL-6 protein and elevation of mRNA whereas LIF or CT-1 did not. IL-6 mRNA levels and protein secretion were reduced in osteoblasts by costimulation with DEX. These results show that mouse OSM, LIF and CT-1 induce osteoclast differentiation and activation, that DEX synergizes with each in this activity, and that mouse OSM induces responses in osteoblasts that are not shown by LIF or CT-1. Collectively these data suggest an important role of these cytokines in osteoporosis caused by high levels of corticosteroid.
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PMID:Stimulation of osteoclast differentiation in vitro by mouse oncostatin M, leukaemia inhibitory factor, cardiotrophin-1 and interleukin 6: synergy with dexamethasone. 1084 36

Peripheral blood monocytes are common precursor cells of dendritic cells (DCs) and macrophages. We have searched for factors with the potential to regulate the differentiation of monocytes to DCs and macrophages. When CD14+ monocytes are cultured with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL) 4, the CD14+CD1a- population, which consists of macrophages, was found in the serum-containing cultures but not in the serum-free cultures. Addition of IL-6 receptor-neutralizing monoclonal antibody (mAb) or gp130-neutralizing mAb to the serum-containing cultures resulted in a decreased population of CD14+CD1a- cells. An increase in the CD14+CD1a- population with reduction in CD14-CD1a+ DCs was observed with the addition of IL-6 to cultures, whereas IL-11, leukaemia inhibitory factor, oncostatin M or macrophage colony-stimulating factor did not affect the differentiation of monocytes in the presence of GM-CSF plus IL-4. This effect of IL-6 was blocked by tumour necrosis factor alpha (TNF-alpha), lipopolysaccharide (LPS), IL-1beta, CD40 ligand (CD40L) and transforming growth factor beta1 (TGF-beta1). Among these factors, TNF-alpha was most potent in interfering with the action of IL-6. These results suggest that IL-6 inhibits the differentiation of monocytes to DCs by promoting their differentiation toward macrophages, which is modulated by factors such as TNF-alpha, LPS, IL-1beta, CD40L and TGF-beta1.
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PMID:Activity of interleukin 6 in the differentiation of monocytes to macrophages and dendritic cells. 1084 14

1. Leukaemia inhibitory factor (LIF) is a 180 amino acid single-chain protein, named after its effect on haematopoietic cells. Leukaemia inhibitory factor belongs to a group of cytokines that includes ciliary neurotrophic factor, interleukin (IL)-6, IL-11, cardiotrophin-1 and oncostatin M. All group members use the gp130 signal transducing subunit for intracellular signalling, but show differences in biological effect. 2. Research over the past 6-8 years has shown LIF to have potent neuromuscular activity. In vitro and in vivo studies on axotomy and nerve crush models demonstrate a powerful effect of LIF in enhancing the survival of both motor and sensory neurons, while reducing denervation-induced muscle atrophy. In models of both axotomy induced neuronal death and in the wobbler mouse, LIF is active at doses as low as 1 microgram/kg delivered systemically. 3. In muscle, LIF will increase the rate of muscle regeneration in vivo when applied exogenously after injury and will stimulate intrinsic muscle repair following its targeted release to dystrophic muscle in the mdx mouse. Leukaemia inhibitory factor may also have a role as an adjunct to myoblast transfer therapy, with studies showing that the transplantation of genetically competent myoblasts into mdx mouse muscle is enhanced when cells are injected with LIF. 4. Distribution and pharmacokinetic studies have been conducted in primates with doses of 20 micrograms/kg recombinant human LIF given subcutaneously over 2 weeks tolerated without major side effects. 5. A pharmaceutical form of recombinant human LIF (AM424; AMRAD Operations, Richmond, Victoria, Australia) entered human clinical trials during 1997 and a phase I clinical trial in healthy volunteers has been completed. A phase I repeat dose study has also been completed in cancer patients undergoing chemotherapy. The primary indication for a phase II study is the treatment of chemotherapy induced peripheral neuropathy. Other potential indications include muscle wasting diseases, acute nerve trauma and motor neuron disease. 6. The role of LIF in modulating nerve loss should make it an ideal candidate for the treatment of a number of neurological conditions. The phase I study represents the first trial in a programme for the clinical development of AM424.
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PMID:AM424: history of a novel drug candidate. 1087 17

The release of PGE(2) and nitric oxide (NO) from the respiratory epithelium may act to dampen inflammation. In other tissues, oncostatin M (OSM), a potent inducer of epithelial antiproteases, has also been shown to interact with IL-1beta to stimulate PGE(2) release. However, whether OSM interacts with pro-inflammatory cytokines and proteases in the production of anti-inflammatory eicosanoids and NO from airway epithelium is unknown. The effect of OSM and the related cytokine leukaemia inhibitory factor (LIF) on PGE(2) and NO production by the respiratory epithelial cell line, A549 in response to pro-inflammatory cytokines as well as protease-rich house dust mite (HDM) fractions and a protease-deficient rye grass pollen extract was examined by immunohistochemistry, cell culture, ELISA and enzyme-immunoassay. Cells treated with a mixture of IL-1beta, IFNgamma and LPS for 48 h produced a 9 fold increase in PGE(2) and a 3 fold increase in NO levels (both P<0.05). Both OSM and LIF were without effect. However, OSM added together with the cytokine mixture synergistically enhanced PGE(2) production (22 fold, P<0.05). OSM also synergistically enhanced PGE(2) production in response to a cysteine protease-enriched, but not serine protease-enriched HDM fraction (P<0.05). Rye grass extract, neither alone nor in combination with OSM, induced PGE(2) or NO production, although it did induce the release of GM-CSF. These observations suggest that OSM is an important co-factor in the release of PGE(2) and NO from respiratory epithelial cells and may play a role in defense against exogenous proteases such as those derived from HDM.
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PMID:Oncostatin M synergises with house dust mite proteases to induce the production of PGE(2) from cultured lung epithelial cells. 1101 96

Bone tissue is continually being remodelled according to physiological circumstances. Two main cell populations (osteoblasts and osteoclasts) are involved in this process, and cellular activities (including cell differentiation) are modulated by hormones, cytokines and growth factors. Within the last 20 years, many factors involved in bone tissue metabolism have been found to be closely related to the inflammatory process. More recently, a cytokine family sharing a common signal transducer (gp130) had been identified, which appears to be a key factor in bone remodelling. This family includes interleukin 6, interleukin 11, oncostatin M, leukaemia inhibitory factor, ciliary neurotrophic factor and cardiotrophin-1. This paper provides an exhaustive review of recent knowledge on the involvement of gp130 cytokine family in bone cell (osteoblast, osteoclast, etc.) differentiation/activation and in osteoarticular pathologies.
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PMID:gp130 Cytokine family and bone cells. 1102 60

This study investigated the ability of normal human osteoblasts (hOb) and osteogenic sarcoma cells (MG-63 and SaOS2) to produce gelatinases and undergo modulation by interleukin 1beta (IL-1beta), interleukin 6 (IL-6), oncostatin M (OSM), leukaemia inhibitory factor (LIF), growth hormone (GH) and insulin-like growth factor-I (IGF-I). Gelatinase activities were determined by zymogaphy, and a quantitative analysis was performed by ELISA. The MMP-2 activities of the three cell lines were significantly increased in the presence of IL-1beta and IL-6, but no modulation of MMP-2 activities was observed in the presence of OSM, LIF and GH. IGF-I increased the activity released by SaOS2 and hOb, but no modulation was detectable in MG-63 cell conditioned medium. An upmodulation of pro-MMP-2 secretion by SaOS2 and hOb was observed for all soluble factors used, whereas an upmodulation of pro-MMP-2 secretion by MG-63 was observed only in the presence of IL-1beta, IL-6 and IGF-I. Thus, osteoblastic cells modulated by cytokines can be involved in bone resorption as a result of the protease activities released.
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PMID:Modulation by soluble factors of gelatinase activities released by osteoblastic cells. 1105 27


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