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)

Plasma fibrinogen is synthesized primarily in hepatocytes and assembly of the three component chains (A alpha, B beta, and gamma) into its final form as a six-chain dimer (A alpha, B beta, gamma)2 occurs rapidly in the lumen of the endoplasmic reticulum (ER). Assembly takes place in a stepwise manner with single chains interacting with each other to form A alpha-gamma and B beta-gamma complexes. The two-chain complexes then acquire another chain to form half-molecules (A alpha, B beta, gamma)1, which in a final step are linked to form the six-chain (A alpha, B beta, gamma)2 complex. As with other secreted glycoproteins, N-linked glycosylation of B beta and gamma chains commences in the ER and is completed in Golgi organelles. Sulfation and phosphorylation occur at post-ER stages of the secretory process. Since some ER chaperones coisolate with nascent fibrinogen chains they have been implicated in assisting chain assembly. Studies with recombinant systems, using deletion and substitution mutants, indicate that initial chain assembly depends on hydrophobic interactions present in the C-terminal half of the coil-coil domains and that inter- and intra-disulfide bonds that stabilize fibrinogen are needed to complete chain assembly. Not all the chains that are synthesized are assembled into fibrinogen and the unassembled chains are not secreted. HepG2 cells contain surplus A alpha and gamma chains that accumulate as free gamma chains and as an A alpha-gamma complex. A alpha-gamma is degraded by lysosomes whereas the gamma chain is degraded by the proteasome-ubiquitin system. Studies with expression of single chains by COS cells confirm that gamma and B beta are hydrolyzed by proteasomes and indicate that A alpha is degraded partially both by lysosomes and proteasomes. The role of surplus chains in regulating fibrinogen assembly is not understood but overexpression of any one chain, elicited by transfection of HepG2 cells, results in the upregulation of the other two genes, increased fibrinogen synthesis and secretion, and maintenance of surplus intracellular A alpha and gamma chains. HepG2 cells, programmed in this manner to increase basal fibrinogen expression, have higher HMG-CoA reductase mRNA levels, enhanced cholesterol and cholesterol ester synthesis, and increased secretion of apolipoprotein B (apoB). Overexpression of basal levels of fibrinogen does not affect synthesis of other acute phase proteins. Enhanced secretion of apoB is due to diminished degradation of nascent apoB by proteasomes and not to increased expression. Increased secretion of apoB is associated with increased basal expression of fibrinogen and is not affected when fibrinogen expression is stimulated by interleukin-6. In HepG2 cells, a feedback mechanism exists and extracellular sterols specifically downregulate expression of the three fibrinogen genes. These studies link, at the cellular level, basal fibrinogen expression with lipid metabolism.
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PMID:Fibrinogen biosynthesis. Assembly, intracellular degradation, and association with lipid synthesis and secretion. 1146 May 6

Recent advances in our understanding of the molecular regulation of myeloma cells suggest novel strategies for treating multiple myeloma. Some myeloma cells express a 69 kD variant of Ku86, a heterodimer subunit that is essential for double-stranded DNA break repair. Presence of the variant impairs DNA repair; therefore normal Ku86 in myeloma cells confers resistance to therapy and may represent a therapeutic target. The upregulation of NF-kappaB-dependent interleukin-6 (IL-6) transcription and secretion that occurs following adhesion of myeloma cells to bone marrow stromal cells (BMSCs) may serve as a potential therapeutic target, as IL-6 is a growth and survival factor for myeloma cells. Accordingly, proteasome inhibitors inhibit activation of NF-kappaB and induce apoptosis of myeloma cells; they also inhibit the NF-kappaB-dependent up-regulation of IL-6 in BMSCs and related paracrine growth of adherent tumor cells. Therapeutic strategies may also target the mitogen-activated protein kinase (MAPK) pathway that is thought to mediate the IL-6-induced proliferation of myeloma cells. Vascular endothelial growth factor (VEGF) is also upregulated by adhesion of myeloma cells to BMSCs and may serve as a growth and/or survival factor for myeloma cells; preliminary studies suggest that VEGF receptor inhibitors may block proliferation of tumor cells. Thalidomide was recently used successfully to treat myeloma in patients whose disease was refractory to conventional treatment. An enhanced understanding of the mechanisms of action of thalidomide may result in the development of analogues with enhanced potency and fewer side effects. The potential mechanisms of action of thalidomide are reviewed, including antiangiogenic effects; direct effects of thalidomide on the growth and survival of myeloma cells and BMSCs; modulation of adhesive interactions; and regulation of secretion and bioactivity of cytokines. Immune-based strategies for treating multiple myeloma are also reviewed. Therapeutic obstacles include excessive toxicity after allografting, contaminating tumor cells in autografts, and the persistence of minimal residual disease (MRD) after high-dose therapy followed by allogenic or autologous stem cell transplantation. Allografting can be performed safely in myeloma, donor lymphocyte infusions (DLI) may effectively treat relapsed myeloma post allografting; and use of CD4+ T cell-enriched DLI may reduce the risk of graft-versus-host disease. Treatment with autografting is frequently compromised by MRD in the autograft and in the patient post myeloablative therapy. Adenoviral purging prior to autotransplantation and in vivo and ex vivo stimulation of autoimmune cells are discussed as potential approaches to address these problems.
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PMID:Novel biologically based therapies for myeloma. 1150 80

This review discusses the evolution of novel diagnostic and treatment strategies for multiple myeloma based upon increased understanding of basic disease pathogenesis. Although myeloma has remained an incurable illness to date, these new developments will derive treatments to improve outcome and achieve eventual cure. In Section I, Dr. Kyle reviews the results of current therapy for multiple myeloma, including high dose therapy and stem cell transplantation which have proven to achieve improved response rates, event-free, and overall survival. Supportive therapy, such as erythropoietin to treat disease-related anemia, and methods of prophylaxis against infection, which both lessen toxicities of treatment and improve quality of life for patients, are also addressed. In Section II, Dr. Dalton with Drs. Landowski, Shain, Jove and Hazlehurst discusses mechanisms of drug resistance in myeloma, with emphasis on novel treatment approaches to prevent development of drug resistance and to overcome drug resistance. Laboratory studies delineating mechanisms whereby myeloma cells resist drug-induced apoptosis provide the framework for related treatment protocols for patients with refractory disease. In Section III, Dr. Berenson reviews the management of complications in bone, which occur in the majority of patients with myeloma and are the major cause of decreased quality of life. New insights into the mediators of bone resorption and new bone formation in the marrow milieu have already derived effective bisphosphonate therapy. These drugs not only reduce bone complications and related pain, thereby improving quality of life, but also may have intrinsic anti-tumor activity by virtue of inducing tumor cell adherence to marrow, reducing interleukin-6 secretion, inducing tumor cell apoptosis, or inhibiting angiogenesis. In the last section, Dr. Anderson explores the potential for future therapies which offer great promise to improve patient outcomes. First, drugs which alter the marrow microenvironment include thalidomide and its derivative immunomodulatory drugs, which act directly on tumor cells to induce apoptosis or G1 growth arrest, alter tumor cell adhesion to marrow stroma, inhibit angiogenesis, and trigger a cellular anti-tumor response. The proteasome inhibitors both act directly on tumor cells and also inhibit the transcription factor NFkappaB-dependent upregulation of IL-6 secretion triggered by tumor cell adhesion. Second, delineation of both growth and apoptotic pathways has derived novel treatment strategies. Third, the preclinical basis and early clinical trial results using vaccination and adoptive immunotherapy to harness autoimmune and alloimmune anti-myeloma responses are presented. This review sets the stage for an evolving new biologically based treatment paradigm in myeloma targeting both the tumor and its microenvironment to improve outcome and achieve eventual cure.
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PMID:Multiple Myeloma: New Insights and Therapeutic Approaches. 1170 40

The 26S proteasome regulates protein turnover in eukaryotic cells. This is relevant in human cancer because the cell cycle, tumor growth, and survival are governed by a large repertoire of intracellular proteins that are regulated by the ubiquitin-mediated proteasome degradative pathway. In the development of new antitumor agents whose mechanisms are distinct from currently available therapies, we have discovered a potent, selective inhibitor of the proteasome: PS-341, a dipeptide boronic acid. Compared with normal cells, cancer cells--and specifically myeloma--treated with PS-341 are differentially sensitive to proteasome inhibition and apoptosis. A unique feature of PS-341 involves the inhibition of nuclear factor (NF)-kappaB activation through stabilization of the inhibitor protein IkappaB. Myeloma cells depend on NF-kappaB-mediated transcription of cytokine growth factor interleukin-6, angiogenesis through vascular endothelial growth factor, and the cell adhesion molecule VCAM-1 for adherence of the plasma cells to the stromal tissue in bone marrow. At low nanomolar concentrations, PS-341 is highly effective in abrogating the transcription of these genes, which are under the direct regulation of NF-kappaB. Moreover, PS-341 appears to synergize with dexamethasone in myeloma cell culture, which may prove to be of additional benefit clinically. The safety profile in phase I trials of PS-341 in patients with cancer appears encouraging. Because proteasome inhibition with PS-341 results in potent antitumor activity in vitro, PS-341 may offer a promising new approach to treating otherwise fatal malignancy.
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PMID:Proteasome inhibition in cancer: development of PS-341. 1174 Aug 19

Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells in the bone marrow caused primarily by failure of normal homeostatic mechanisms to prevent the expansion of postgerminal center plasma cells. We have examined the molecular mechanisms that promote the survival of MM cells and have identified a key role for myeloid cell factor-1 (Mcl-1), an antiapoptotic member of the Bcl-2 family. These experiments were initiated by the observation that MM cells were exquisitely sensitive to culture in the presence of actinomycin D: caspase activation occurred within 3 hours of treatment and cells were not protected by interleukin-6, the main MM cell growth and survival factor. Actinomycin D-induced apoptosis was blocked by proteasome inhibitors, suggesting that a labile protein was required for MM cell survival. Further analysis demonstrated that Mcl-1 was likely to be the labile factor governing MM cell survival. Mcl-1 protein levels decreased rapidly after culture in the presence of actinomycin D in concordance with effector caspase activation, but addition of proteasome inhibitors reversed the loss of Mcl-1 and maintained cell viability. The levels of other antiapoptotic proteins, including Bcl-2 and members of the inhibitors-of-apoptosis family, were unaffected by these interventions. Furthermore, Mcl-1 antisense oligonucleotides caused a rapid down-regulation of Mcl-1 protein levels and the coincident induction of apoptosis, whereas overexpression of Mcl-1 delayed actinomycin D-induced apoptosis with kinetics that correlated with expression levels of Mcl-1. These data indicate that Mcl-1 expression is required for the survival of MM cells and may represent an important target for future therapeutics.
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PMID:Myeloid cell factor-1 is a critical survival factor for multiple myeloma. 1187 56

A role for cytokine regulated proteins in epithelial cells has been suggested in the pathogenesis of inflammatory bowel diseases (IBD). The aim of this study was to identify such cytokine regulated targets using a proteomic functional approach. Protein patterns from (35)S-radiolabeled homogenates of cultured colon epithelial cells were compared before and after exposure to interferon-gamma, interleukin-1beta and interleukin-6. Proteins were separated by two-dimensional polyacrylamide gel electrophoresis. Both autoradiographies and silver stained gels were analyzed. Proteins showing differential expression were identified by tryptic in-gel digestion and mass spectrometry. Metabolism related proteins were also investigated by Western blot analysis. Tryptophanyl-tRNA synthetase, indoleamine-2,3-dioxygenase, heterogeneous nuclear ribonucleoprotein JKTBP, interferon-induced 35kDa protein, proteasome subunit LMP2 and arginosuccinate synthetase were identified as cytokine modulated proteins in vitro. Using purified epithelial cells from patients, overexpression of indoleamine-2,3-dioxygenase, an enzyme involved in tryptophan metabolism, was confirmed in Crohn's disease as well as in ulcerative colitis, as compared to normal mucosa. No such difference was found in diverticulitis. Potentially, this observation opens new avenues in the treatment of IBD.
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PMID:Proteomic analysis of cytokine induced proteins in human intestinal epithelial cells: implications for inflammatory bowel diseases. 1198 29

Bradykinin (BK) B(1) receptors are thought to exert a pivotal role in maintaining and modulating inflammatory processes. They are not normally present under physiological situations but are induced under physiopathological conditions. In isolated human umbilical vein (HUV), a spontaneous BK B(1) receptor up-regulation and sensitization process has been demonstrated. Based on pyrrolidine-dithiocarbamate inhibition, it has been proposed that this phenomenon is dependent on nuclear factor-kappaB (NF-kappaB) activation. The aim of this study was to further evaluate the NF-kappaB pathway involvement on BK B(1) receptor sensitization in isolated HUV, using several pharmacological tools. In 5-h incubated rings, either the I-kappaB kinase inhibitor 3-(4-methylphenylsulfonyl)-2-propenenitrile (Bay 11-7082) or the proteasome activity inhibitor Z-Leu-Leu-Leu-CHO (MG-132) inhibited the development of the BK B(1) receptor-sensitized contractile responses. Furthermore, pro-inflammatory cytokine interleukin-6 (IL-6) produced a leftward shift of the concentration-response curve to the BK B(1) receptor agonist, whereas anti-inflammatory cytokines interleukin-4 (IL-4) and tumor growth factor-beta1 (TGF-beta1) produced a rightward shift of the responses to des-Arg(9)-BK in our preparations. Taken together, these results point to NF-kappaB as a key intermediary in the activation of the expression of BK B(1) receptor-sensitized responses in HUV and support the role of inflammatory mediators in the modulation of this process.
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PMID:Further pharmacological evidence of nuclear factor-kappa B pathway involvement in bradykinin B1 receptor-sensitized responses in human umbilical vein. 1202 27

The ascites hepatoma Yoshida AH-130 induces loss of body weight and tissue waste. Tumour necrosis factor alpha (TNF-alpha) plays a pivotal role in the pathogenesis of muscle wasting in this model system, but other cytokines, such as interleukin-6, may be involved. In order to verify whether a combined anticytokine treatment may synergistically counteract muscle protein degradation, tumour bearing rats were treated with pentoxyfilline (PTX, an inhibitor of TNF-alpha synthesis), or with suramin (SUR, an antiprotozoal drug blocking the peripheral action of several cytokines including IL-6 and TNF-alpha), or both the drugs, and the effects on muscle proteolytic systems were assessed. Muscle protein loss in the AH-130-bearing rats was associated with increased activity of both the ATP-ubiquitin- and the calpain- dependent proteolytic pathways (246% and 230% of controls, respectively). Both PTX and SUR, either alone or in combination, prevented the depletion of muscle mass and significantly reduced the activity of muscle proteolytic systems. In particular, treatment with SUR, either alone or with PTX, induced a decrease in enzymatic activities to values similar to those of controls. The results obtained in the present paper demonstrate that: (i) muscle depletion in this model is indeed associated with increased proteasome- and calpain-dependent proteolysis, as previously suggested by increased mRNA expression of molecules pertaining to both pathways; (ii) anticytokine treatments effectively reduce muscle protein loss by down-regulating the activity of at least two major proteolitic systems; (iii) SUR is more effective than PTX in reducing the activity of proteolytic systems, possibly because of its multiple anticytokine action.
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PMID:Anticytokine treatment prevents the increase in the activity of ATP-ubiquitin- and Ca(2+)-dependent proteolytic systems in the muscle of tumour-bearing rats. 1220 Jan 6

Proteasome inhibitor PS-341 induces growth arrest and apoptosis of multiple myeloma (MM) cells via inactivation of nuclear factor kappaB (NF-kappaB) in vitro. In addition, recent clinical studies of PS-341 have demonstrated some objective responses in individuals with relapsed, refractory MM. However, the activity of PS-341 against non-hematological malignancies remains to be fully elucidated. In this study, we found that PS-341 induced growth arrest and apoptosis of androgen-dependent human prostate cancer LNCaP cells in conjunction with markedly up-regulated levels of p21(waf1) and p53. In addition, we found that PS-341 down-regulated both 5alpha-dihydrotestosterone (DHT)- and interleukin-6 (IL-6)-induced expression of prostate-specific antigen (PSA) as measured by western blot analysis. PS-341 down-regulated basal levels of the androgen receptor (AR) in the nucleus; however, it did not affect DHT-induced nuclear translocation of AR in these cells. Reporter assays using a series of promoters of the PSA gene showed that down-regulation of PSA by PS-341 was caused by inhibition of the transcriptional activity of the androgen receptor response element (ARE) in these cells. Taken together, the results indicate that PS-341 induced growth arrest and apoptosis of LNCaP cells by blockade of the AR signaling pathway. The proteasome may be a molecular target for treatment of a variety of cancers including prostate cancer.
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PMID:Proteasome inhibitor PS-341 down-regulates prostate-specific antigen (PSA) and induces growth arrest and apoptosis of androgen-dependent human prostate cancer LNCaP cells. 1501 28

Circulating interleukin-6 (IL-6), insulin, and free fatty acid (FFA) concentrations are associated with impaired insulin action in obese and type 2 diabetic individuals. However, a causal relationship between elevated plasma FFAs and IL-6 has not been shown. Because skeletal muscle represents a major target of impaired insulin action, we studied whether FFAs may affect IL-6 expression in human myotubes. We demonstrate that specifically saturated FFAs, e.g. palmitate (0.25 mm), induce IL-6 mRNA expression and protein secretion by a proteasome-dependent mechanism that leads to a rapid and chronic activation of nuclear factor-kappaB. Insulin, high glucose concentrations, or unsaturated FFAs did not activate IL-6 expression. In fact, the unsaturated FFA linoleate inhibited palmitate-induced IL-6 production. Because inhibition of palmitate metabolism by the acyl-CoA synthetase inhibitor triacsin C did not abolish IL-6 expression, it appears that the palmitate molecule per se exerts the observed effects. Furthermore, we show that in human myotubes, IL-6 activates the phosphorylation of signal transducer and activator of transcription 3 in concentrations similar to hepatocytes. However, no inhibitory effect of IL-6 on insulin action, determined as phosphatidylinositol 3-kinase association with insulin receptor substrate-1, Akt phosphorylation, and glycogen synthesis, was detected. We conclude that IL-6 expression may be modulated by the composition of circulating FFA, e.g. by diet, and that skeletal muscle cells could be target cells for IL-6.
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PMID:Palmitate, but not unsaturated fatty acids, induces the expression of interleukin-6 in human myotubes through proteasome-dependent activation of nuclear factor-kappaB. 1502 33


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