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

PL-21 is a promyelocytic leukemia cell line that produces plasminogen activator inhibitor 2 (PAI-2). Differentiation-linked expression of PAI-2 was investigated by adding cell-differentiation promoting agents [such as phorbol myristate acetate (PMA), retinoic acid (RA), dexamethasone (Dex), and recombinant cytokines, including tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta), granulocyte-colony stimulating factor (G-CSF), and interleukin-6 (IL-6)] into the culture medium of PL-21 cells. PAI-1 and PAI-2 antigens were measured by an enzyme-linked immunoassay. The PAI-1 antigen, however, became detectable only after stimulation. The presence of PAI-2 antigen was further verified by immunoblotting using a monoclonal antibody against PAI-2 purified from a PL-21 culture medium. PAI activity both in the culture medium and in the cell lysate increased approximately 70-fold after exposure to PMA. Both PAI-1 and PAI-2 antigens increased, but the amount of the latter in the culture medium and in the cell lysate was approximately 10 times and 2,500 times, as much, respectively, as that of the former. Dex also increased the intracellular PAI activity approximately 6-fold, parallel with PAI-2 antigen. PAI-1 antigen increased only slightly in the culture medium but not in the cell lysate after Dex-stimulation. As with the case of PMA, TNF-alpha and IL-6 induced PL-21 cells to macrophage-like cells, but did not affect the PAI activity. Thus, the increase of the PAI-2 production by PMA may not necessarily depend on differentiation into macrophages. Other cytokines examined did not increase the PAI activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Dexamethasone and phorbol ester, but not cytokines, increase the production of plasminogen activator inhibitor type-2 in the PL-21 human promyelocytic leukemia cell line. 177 17

Differentiation-linked expression of plasminogen activator inhibitor-2 (PAI-2) was investigated by adding cell-differentiation promoting agents [such as phorbol myristate acetate (PMA), retinoic acid, dexamethasone (Dex), and recombinant cytokines, including tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta, granulocyte-colony stimulating factor, and interleukin-6 (IL-6)] into the culture medium of a promyelocytic leukemia cell line PL-21. PAI activity both in the culture medium and in the cell lysate increased approximately 70-fold after exposure to PMA. Both PAI-1 and PAI-2 antigens increased, but the amounts of the latter in the culture medium and in the cell lysate were approximately 10 times and 2,500 times, as much, respectively, as those of the former. Dex also increased the intracellular PAI activity approximately 6-fold, parallel with PAI-2 antigen. PAI-1 antigen increased only slightly in the culture medium but not in the cell lysate after Dex-stimulation. As with the case of PMA, TNF-alpha and IL-6 induced PL-21 cells to macrophage-like cells, but did not affect the PAI activity. Thus, the increase of the PAI-2 production by PMA may not necessarily depend on differentiation into macrophages. Other cytokines examined did not increase the PAI activity. PAI-2 antigen was demonstrated in the cell lysates of various leukemia cells by Western blotting technique using a monoclonal antibody against the PAI-2 purified from PL-21 culture medium. PAI-2 antigen was frequently detected in the plasmas from the patients whose peripheral leukocytes were more than 10,000/microliters.
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PMID:[Production and secretion of the plasminogen activator inhibitor type-2 in a leukemia cell line]. 187 Feb 66

A high serum concentration of lipoprotein(a) [Lp(a)] is a significant and independent risk factor for cardiovascular disease. We examined the effects of agents on the transcriptional activity of the apolipoprotein(a) [apo(a)] gene promoter and determined whether drugs identified by this assay would affect the serum concentration of Lp(a) in vivo. All-trans-retinoic acid (ATRA) and interleukin-6 increased the transcriptional activity of the apo(a) gene promoter 2.1- and 2.5-fold, respectively, whereas danazol reduced activity to 76% of the control value. Triiodothyronine had no effect on transcriptional activity. Treatment of two acute promyelocytic leukemia patients with ATRA induced maximal 2.7- and 3.2-fold increases in serum Lp(a) concentrations, respectively. Thus, the in vitro luciferase assay system is capable of identifying agents that affect the serum concentration of Lp(a) and thus may prove beneficial in the screening of new drugs for treatment of individuals with high serum Lp(a) concentrations.
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PMID:An in vitro system for identifying agents capable of changing serum lipoprotein(a) concentration by regulating the transcriptional activity of the apolipoprotein(a) gene promoter. 887 54

Acute promyelocytic leukemia (APL) is characterized cytogenetically by the presence of a reciprocal translocation between chromosomes 15 and 17 [t(15;17)(q22-q24;q11-q21)] in the bone marrow cells in the majority of patients. Cytogenetic evaluation of bone marrow cultures from patients with APL is often technically difficult, due to frequent difficult marrow aspiration and the suboptimal quality of cytogenetic preparations. This has important implications for the cytogenetic detection of residual disease. This study examined the proliferative ability of the recombinant human growth factors-stem cell factor (SCF), interleukin-6 (IL-6), interleukin-3 (IL-3), and granulocyte macrophage-colony stimulating factor (GM-CSF)-to determine if they would provide a consistent improvement over the standard cytogenetic culturing techniques in terms of mitotic index (MI). In all cases, the MI of the growth factor stimulated cultures showed a considerably higher (3.5-198 fold) and statistically significant (p < 0.01) increase compared to the unstimulated cultures. We conclude that the use of recombinant human growth factors is potentially an effective way of increasing the MI in bone marrow cultures from APL patients for the purposes of diagnosis and residual disease detection.
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PMID:Combination of SCF, IL-6, IL-3, and GM-CSF increases the mitotic index in short term bone marrow cultures from acute promyelocytic leukemia (APL) patients. 890 73

Transglutaminase is a calcium-dependent enzyme that catalyzes an amine incorporation and a cross-linking of proteins. Intracellular transglutaminase is induced when human promyelocytic leukemia HL-60 cells are treated with retinoic acid and human hepatoblastoma HepG2 cells, with interleukin-6. To find whether the intracellular reaction catalyzed by transglutaminase increased when the enzyme is induced in these cells, the transglutaminase-catalyzed incorporation of 14C-labeled methylamine into cellular proteins was measured. The incorporation level of the labeled methylamine into proteins of HL-60 and HepG2 cells did not increase after the transglutaminase had been induced. The presence of the calcium ionophore A23187 did not affect these results. These findings suggested that even after the enzyme induction the catalytic action of intracellular transglutaminase is maintained at a constant level in these cells by unknown regulatory mechanism(s).
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PMID:Analysis of catalytic action of transglutaminase induced in human promyelocytic leukemia (HL-60) and human hepatoblastoma (HepG2) cells. 898 79

We have previously identified and cloned an alternatively spliced form of human interleukin-6 mRNA lacking exon II, which encodes amino acid residues known to be important in gp130-mediated signal transduction pathways. We expressed and purified the recombinant protein (rIL6-alt) resulting from this alternatively spliced mRNA and now report the initial characterization of its biologic activities with comparison to full length IL6 (rIL6-full). rIL6-alt was found to have 10(4) to 10(5) fold less activity in proliferation assays with 7TD1 murine plasmacytoma cells and did not competitively inhibit the stimulatory activity of rIL6-full. In addition, like rIL6-full, rIL6-alt had antiproliferative activity toward M1 murine myeloblast cells and was 10-200-fold less active than rIL6-full. In contrast, in assays with human HL60 promyelocytic leukemia cells, rIL6-alt had greater antiproliferative activity than rIL6-full and more strongly upregulated phagocytosis as well as surface expression of the differentiation antigen CD11b. rIL6-full and rIL6-alt upregulated the level of lysozyme mRNA in HL60 cells approximately equally. These findings suggest that IL6-alt, which lacks amino acid residues encoded by the second exon of the gene, is not a natural inhibitor of IL6-full but may be relatively tissue specific and may play a role in modulation of hematopoietic cell growth and differentiation.
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PMID:Hematopoietic differentiation activity of a recombinant human interleukin-6 (IL-6) isoform resulting from alternatively spliced deletion of the second exon. 1039 9

Granulocyte colony-stimulating factor (G-CSF) is a cytokine that regulates the proliferation, differentiation and survival of cells in the granulocytic lineage. In this study, however, we found that G-CSF or interleukin-6 (IL-6) induced UF-1, a human acute promyelocytic leukemia cell line, into apoptosis that was confirmed by morphological features and DNA fragmentation. This rare response is demonstrated for the first time with human acute promyelocytic leukemia cell line. The apoptosis induced by G-CSF or IL-6 was not preceded by terminal differentiation characterized by morphological maturation, capability to reduce nitroblue tetrazolium, or surface CD11b expression. Interestingly, Western blot analysis revealed that the stimulation of UF-1 with either G-CSF or IL-6 resulted in excessive activation of both signal transducer and activator of transcription 3alpha (Stat3alpha) and Stat3beta. Furthermore, an additional 18 kDa Bax-related protein was expressed by the stimulation of G-CSF or IL-6, while Bcl-2 and Bcl-X proteins remained unchanged. These findings suggest that UF-1 may be a valuable tool in investigating the aberrant regulation of apoptosis, especially the Stat3 involvement in the mechanism of apoptosis induction.
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PMID:G-CSF induces apoptosis of a human acute promyelocytic leukemia cell line, UF-1: possible involvement of Stat3 activation and altered Bax expression. 1062 10

It has been shown that retinoic acid (RA) induced the expression of interleukin-6 (IL-6) in human acute promyelocytic leukemia HL-60 cells. In the present study, we examined the ability of RA to induce the expression of gp130, the signal-transducing receptor component for IL-6, in HL-60 and a RA-supersensitive cell line HL-60/S4. We found that RA induced the expression of gp130, at both the mRNA and protein levels, in HL-60 and HL-60/S4 cells. Interestingly, the induction of gp 130 expression observed in the RA-supersensitive HL-60/S4 cells was much more pronounced than that observed in HL-60 cells. Furthermore, activation of the RA-induced gp130 by exogenous IL-6 potentiated the differentiating effects of RA. The synergistic effects observed for IL-6 and RA was also much stronger in HL-60/S4 cells than in HL-60 cells. Our findings suggest that the differentiating effects of RA may partially be mediated by the up-regulation of IL-6/gp130 signaling in HL-60 and HL-60/S4 cells.
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PMID:IL-6 enhanced the retinoic acid-induced differentiation of human acute promyelocytic leukemia cells. 1069 98

Multiple myeloma (MM) is a clonal B-cell malignancy characterized by slow-growing plasma cells in the bone marrow (BM). Patients with MM typically respond to initial chemotherapies; however, essentially all progress to a chemoresistant state. Factors that contribute to the chemorefractory phenotype include modulation of free radical scavenging, increased expression of drug efflux pumps, and changes in gene expression that allow escape from apoptotic signaling. Recent data indicate that arsenic trioxide (As(2)O(3)) induces remission of refractory acute promyelocytic leukemia and apoptosis of cell lines overexpressing Bcl-2 family members; therefore, it was hypothesized that chemorefractory MM cells would be sensitive to As(2)O(3). As(2)O(3) induced apoptosis in 4 human MM cell lines: 8226/S, 8226/Dox40, U266, and U266/Bcl-x(L). The addition of interleukin-6 had no effect on cell death. Glutathione (GSH) has been implicated as an inhibitor of As(2)O(3)-induced cell death either through conjugating As(2)O(3) or by sequestering reactive oxygen induced by As(2)O(3). Consistent with this possibility, increasing GSH levels with N-acetylcysteine attenuated As(2)O(3) cytotoxicity. Decreases in GSH have been associated with ascorbic acid (AA) metabolism. Clinically relevant doses of AA decreased GSH levels and potentiated As(2)O(3)-mediated cell death of all 4 MM cell lines. Similar results were obtained in freshly isolated human MM cells. In contrast, normal BM cells displayed little sensitivity to As(2)O(3) alone or in combination with AA. Together, these data suggest that As(2)O(3) and AA may be effective antineoplastic agents in refractory MM and that AA might be a useful adjuvant in GSH-sensitive therapies. (Blood. 2001;98:805-813)
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PMID:Ascorbic acid enhances arsenic trioxide-induced cytotoxicity in multiple myeloma cells. 1146 82

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is involved in a variety of biological functions. It is essential for the signal transduction of interleukin-6 (IL-6) and related cytokines. In response to IL-6 stimulation STAT3 becomes phosphorylated and translocates into the nucleus where it binds to enhancer sequences of target genes. We found that activated STAT3 is enriched in dot-like structures within the nucleus, which we termed STAT3 nuclear bodies. To examine the dynamics of STAT3 nuclear body formation, a fusion protein of STAT3 and yellow fluorescent protein (YFP) was constructed. Studies in living cells have shown that the appearance of STAT3 nuclear bodies is transient, correlating with the timecourse of tyrosine-phosphorylation of STAT3. Furthermore, we show by fluorescence recovery after photobleaching (FRAP) analysis that STAT3 within nuclear bodies consists of a highly mobile and an immobile fraction. Colocalization studies provided evidence that these bodies are accompanied with CREB binding protein (CBP) and acetylated histone H4, which are markers for transcriptionally active chromatin. Moreover, STAT3 nuclear bodies in HepG2 cells are not colocalized with promyelocytic leukemia oncoprotein (PML)-containing bodies; neither is a sumoylation of activated STAT3 detectable. Taken together, our data suggest that STAT3 nuclear bodies are either directly involved in active gene transcription or they serve as reservoirs of activated STAT3.
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PMID:STAT3 is enriched in nuclear bodies. 1465 76


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