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)

Experimental infection of inbred mouse strains with Candida albicans provides a good model system to identify host genetic determinants that regulate onset of, response to, and ultimate outcome of disseminated candidiasis. The A/J mouse strain is exquisitely sensitive to infection with C. albicans, while the C57BL/6J strain is relatively resistant, as measured by survival following intravenous injection of Candida blastospores. This differential susceptibility is caused by an A/J-specific loss-of-function mutation in the C5 component of the complement pathway. C5 plays several critical roles in host response to infection, including target lysis and phagocyte recruitment. Therefore, to determine which of its functions were required for host resistance to candidiasis, a detailed comparative analysis of pathophysiology and host response to acute C. albicans infection was conducted in A/J and C57BL/6J mice. C5-sufficient C57BL/6J mice were found to succumb late in infection due to severe kidney pathology, typified by fungal replication and robust neutrophil-based inflammatory response associated with extensive tissue damage. In contrast, A/J mice were moribund within 24 h postinfection but displayed little if any kidney damage despite an inability to mobilize granulocytes and a high fungal load in the kidney. Rather, C5 deficiency in A/J mice was associated with higher levels of circulating cytokines tumor necrosis factor alpha, interleukin-6, monocyte chemotactic protein 1 (MCP-1), MCP-5, and eotaxin in response to C. albicans. Transfer of the C5-defective allele from A/J onto a C57BL/6J genetic background in recombinant congenic strain BcA17 recapitulated the phenotypic aspects of the susceptibility of A/J mice to C. albicans, confirming the causative role of C5 deficiency in the dysregulated cytokine response.
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PMID:Dysregulated inflammatory response to Candida albicans in a C5-deficient mouse strain. 1538 88

The stromal compartments of hematopoietic organs (eg, spleen) are known to influence the viability and growth of diseased hematopoietic progenitors. Here we have used Friend murine leukemia virus (F-MuLV)-induced erythroleukemia to investigate factors of the splenic microenvironment that may make it fertile for the expansion and survival of malignant erythroblasts. We found that splenectomized, erythroleukemic mice exhibited extended survival compared with age-matched sham controls. In vitro, the proliferation of primary erythroleukemic cells cocultured with leukemic-derived splenic adherent cells or their conditioned media was found to be significantly higher than that observed in cocultures with healthy-derived adherent splenic cells. Cytokine protein arrays revealed that F-MuLV-infected splenocytes secreted elevated levels of interleukin-6 (IL-6), vascular endothelial growth factor-A (VEGF-A), macrophage chemoattractant protein-5 (MCP-5), soluble tumor necrosis factor receptor-1 (sTNFR1), IL-12p70, tumor necrosis factor-alpha (TNF-alpha), and IL-2 over normal splenocytes. Medium supplemented with both VEGF-A and MCP-5 could sustain proliferation of primary erythroleukemic cells in vitro, and significant proliferative suppression was observed upon addition of neutralizing antibodies to either of these factors. Furthermore, in vivo administration of a neutralizing antibody to VEGF-A extended survival times of erythroleukemic mice in comparison with controls. These findings suggest that VEGF-A and MCP-5 are potentially pivotal paracrine mediators occurring within the diseased splenic microenvironment capable of promoting disease acceleration and expansion of erythroleukemic blasts.
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PMID:The splenic microenvironment is a source of proangiogenesis/inflammatory mediators accelerating the expansion of murine erythroleukemic cells. 1570 19

Transcription regulators STAT1 and STAT2 are key components of the interferon signaling system leading to innate antiviral immunity. The related STAT3 protein is a regulator of interleukin-6-type cytokine signals and can contribute to both cell growth and death important for cancer gene regulation and tumor survival. These three STAT proteins are targeted for proteasome-mediated degradation by RNA viruses in the Rubulavirus genus of the Paramyxoviridae. A single viral protein, the V protein, assembles STAT-specific ubiquitin ligase complexes from cellular components. Simian virus 5 (SV5) targets STAT1, human parainfluenza virus 2 targets STAT2, and mumps virus targets both STAT1 and STAT3. Analysis of the V-dependent degradation complex (VDC) composition and assembly revealed several features contributing to targeting specificity. SV5 and mumps V proteins require STAT2 to recruit the STAT1 target, yet mumps V protein binds STAT3 independent of STAT1 and STAT2. All Rubulavirus V proteins tested require cellular DDB1 to target STATs for degradation but differ in the use of Roc1, which is essential for mumps V STAT3 targeting. Protein interaction analysis reveals that paramyxovirus V proteins can homo- and heterooligomerize and that the conserved cysteine-rich zinc-binding C-terminal domain is necessary and sufficient for oligomerization. Purified SV5 V protein spontaneously assembles into spherical macromolecular particles, and similar particles constitute SV5 and mumps VDC preparations.
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PMID:Composition and assembly of STAT-targeting ubiquitin ligase complexes: paramyxovirus V protein carboxyl terminus is an oligomerization domain. 1605 11

The interleukin-6 (IL-6) family of cytokines is a family of structurally and functionally related proteins, including IL-6, IL-11, leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), and cardiotrophin-1 (CT-1). These proteins are also known as gp130 cytokines because they all share gp130 as a common transducer protein within their functional receptor complexes. Several of these cytokines (LIF, OSM, CNTF, and CT-1) also utilize the LIF receptor (LIFR) as a component of their receptor complex. We have shown that all of these cytokines are capable of activating both the JAK/STAT and p42/44 mitogen-activated protein kinase signaling pathways in 3T3-L1 adipocytes. By performing a variety of preincubation studies and examining the ability of these cytokines to activate STATs, ERKs, and induce transcription of SOCS-3 mRNA, we have also examined the ability of gp130 cytokines to modulate the action of their family members. Our results indicate that a subset of gp130 cytokines, in particular CT-1, LIF, and OSM, has the ability to impair subsequent signaling activity initiated by gp130 cytokines. However, IL-6 and CNTF do not exhibit this cross-talk ability. Moreover, our results indicate that the cross-talk among gp130 cytokines is mediated by the ability of these cytokines to induce ligand-dependent degradation of the LIFR, in a proteasome-independent manner, which coincides with decreased levels of LIFR at the plasma membrane. In summary, our results demonstrate that an inhibitory cross-talk among specific gp130 cytokines in 3T3-L1 adipocytes occurs as a result of specific degradation of LIFR via a lysosome-mediated pathway.
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PMID:Cross-talk among gp130 cytokines in adipocytes. 1609 72

We show that multiple myeloma (MM), the second most commonly diagnosed hematologic malignancy, is responsive to hsp90 inhibitors in vitro and in a clinically relevant orthotopic in vivo model, even though this disease does not depend on HER2/neu, bcr/abl, androgen or estrogen receptors, or other hsp90 chaperoning clients which are hallmarks of tumor types traditionally viewed as attractive clinical settings for use of hsp90 inhibitors, such as the geldanamycin analog 17-AAG. This class of agents simultaneously suppresses in MM cells the expression and/or function of multiple levels of insulin-like growth factor receptor (IGF-1R) and interleukin-6 receptor (IL-6R) signaling (eg, IKK/NF-kappaB, PI-3K/Akt, and Raf/MAPK) and downstream effectors (eg, proteasome, telomerase, and HIF-1alpha activities). These pleiotropic proapoptotic effects allow hsp90 inhibitors to abrogate bone marrow stromal cell-derived protection on MM tumor cells, and sensitize them to other anticancer agents, including cytotoxic chemotherapy and the proteasome inhibitor bortezomib. These results indicate that hsp90 can be targeted therapeutically in neoplasias that may not express or depend on molecules previously considered to be the main hsp90 client proteins. This suggests a more general role for hsp90 in chaperoning tumor- or tissue-type-specific constellations of client proteins with critical involvement in proliferative and antiapoptotic cellular responses, and paves the way for more extensive future therapeutic applications of hsp90 inhibition in diverse neoplasias, including MM.
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PMID:Antimyeloma activity of heat shock protein-90 inhibition. 1623 64

Even apparently healthy patients on dialysis have significant loss of lean body mass. Patients with chronic renal failure without coexisting metabolic acidosis or inflammation have decreased protein turnover, with balanced reduction in protein synthesis and breakdown. However, regional and whole-body protein kinetic studies indicate that hemodialysis (HD) induces net increase in protein breakdown. Whole-body protein turnover studies show that HD is associated with decreased protein synthesis, but proteolysis is not increased. Muscle protein kinetics studies, however, identify enhanced muscle protein breakdown with inadequate compensatory increases in synthesis as the cause of the catabolism. Transmembrane amino acid-transport kinetics studies show that the outward transport is increased more than the inward transport of amino acids during HD. Altered intracellular amino acid transport kinetics and protein turnover during HD could be caused by the loss of amino acids in the dialysate or cytokine activation. Cytokines may be released from peripheral blood mononuclear cells and skeletal muscle during HD. Preliminary evidence indicates that intradialytic increase in cytokines activates the ubiquitin-proteasome pathway. An intradialytic increase in albumin and fibrinogen synthesis is facilitated by interleukin-6 and the constant supply of amino acids derived from skeletal muscle catabolism. Protein anabolism can be induced in end-stage renal disease patients by repletion of amino acids, and perhaps treatment with recombinant human insulin-like growth factor.
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PMID:Amino Acid and protein kinetics in renal failure: an integrated approach. 1653 Jun 7

Pseudomonas aeruginosa secretes several proteases considered as important virulence factors. In this report we present data indicating that two key proinflammatory cytokines, interleukin-6 (IL-6) and IL-8, are substrates for pseudolysin (elastase) and aeruginolysin (alkaline protease). While IL-6 was totally digested by both proteases, a long form of IL-8 (IL-8-77) was first rapidly processed into a 72-residue form with enhanced chemokine activity, then very slowly degraded. Interestingly, aeruginolysin bearing two additional residues at the N-terminus (Leu-Lys-aeruginolysin) in the absence of calcium degraded both IL-6 and IL-8-72 far more efficiently than the shorter form of the enzyme.
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PMID:Interaction of a novel form of Pseudomonas aeruginosa alkaline protease (aeruginolysin) with interleukin-6 and interleukin-8. 1691 41

Second mitochondria-derived activator of caspases (Smac) promotes apoptosis via activation of caspases. Here we show that a low-molecular-weight Smac mimetic LBW242 induces apoptosis in multiple myeloma (MM) cells resistant to conventional and bortezomib therapies. Examination of purified patient MM cells demonstrated similar results, without significant cytotoxicity against normal lymphocytes and bone marrow stromal cells (BMSCs). Importantly, LBW242 abrogates paracrine MM cell growth triggered by their adherence to BMSCs and overcomes MM cell growth and drug-resistance conferred by interleukin-6 or insulinlike growth factor-1. Overexpression of Bcl-2 similarly does not affect LBW242-induced cytotoxicity. Mechanistic studies show that LBW242-induced apoptosis in MM cells is associated with activation of caspase-8, caspase-9, and caspase-3, followed by PARP cleavage. In human MM xenograft mouse models, LBW242 is well tolerated, inhibits tumor growth, and prolongs survival. Importantly, combining LBW242 with novel agents, including tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or the proteasome inhibitors bortezomib and NPI-0052, as well as with the conventional anti-MM agent melphalan, induces additive/synergistic anti-MM activity. Our study therefore provides the rationale for clinical protocols evaluating LBW242, alone and together with other anti-MM agents, to improve patient outcome in MM.
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PMID:Targeting mitochondrial factor Smac/DIABLO as therapy for multiple myeloma (MM). 1703 24

Severe or chronic disease can lead to cachexia which involves weight loss and muscle wasting. Cancer cachexia contributes significantly to disease morbidity and mortality. Multiple studies have shown that the metabolic changes that occur with cancer cachexia are unique compared to that of starvation. Specifically, cancer patients seem to lose a larger proportion of skeletal muscle mass. There are three pathways that contribute to muscle protein degradation: the lysosomal system, cytosolic proteases and the ubiquitin (Ub)-proteasome pathway. The Ub-proteasome pathway seems to account for the majority of skeletal muscle degradation in cancer cachexia and is stimulated by several cytokines including tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, interferon-gamma and proteolysis-inducing factor. Cachexia is particularly severe in pancreatic cancer and contributes significantly to the quality of life and mortality of these patients. Several factors contribute to weight loss in these patients, including alimentary obstruction, pain, depression, side effects of therapy and a high catabolic state. Although no single agent has proven to halt cachexia in these patients there has been some progress in the areas of nutrition with supplementation and pharmacological agents such as megesterol acetate, steroids and experimental trials targeting cytokines that stimulate the Ub-proteasome pathway.
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PMID:Mechanisms of skeletal muscle degradation and its therapy in cancer cachexia. 1745 54

Smoking causes multiple organ dysfunction. The effect of smoking on skeletal muscle protein metabolism is unknown. We hypothesized that the rate of skeletal muscle protein synthesis is depressed in smokers compared with non-smokers. We studied eight smokers (> or =20 cigarettes/day for > or =20 years) and eight non-smokers matched for sex (4 men and 4 women per group), age (65 +/- 3 and 63 +/- 3 yr, respectively; means +/- SEM) and body mass index (25.9 +/- 0.9 and 25.1 +/- 1.2 kg/m(2), respectively). Each subject underwent an intravenous infusion of stable isotope-labeled leucine in conjunction with blood and muscle tissue sampling to measure the mixed muscle protein fractional synthesis rate (FSR) and whole body leucine rate of appearance (Ra) in plasma (an index of whole body proteolysis), the expression of genes involved in the regulation of muscle mass (myostatin, a muscle growth inhibitor, and MAFBx and MuRF-1, which encode E3 ubiquitin ligases in the proteasome proteolytic pathway) and that for the inflammatory cytokine TNF-alpha in muscle, and the concentration of inflammatory markers in plasma (C-reactive protein, TNF-alpha, interleukin-6) which are associated with muscle wasting in other conditions. There were no differences between nonsmokers and smokers in plasma leucine concentration, leucine rate of appearance, and plasma concentrations of inflammatory markers, or TNF-alpha mRNA in muscle, but muscle protein FSR was much less (0.037 +/- 0.005 vs. 0.059 +/- 0.005%/h, respectively, P = 0.004), and myostatin and MAFBx (but not MuRF-1) expression were much greater (by approximately 33 and 45%, respectivley, P < 0.05) in the muscle of smokers than of nonsmokers. We conclude that smoking impairs the muscle protein synthesis process and increases the expression of genes associated with impaired muscle maintenance; smoking therefore likely increases the risk of sarcopenia.
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PMID:Smoking impairs muscle protein synthesis and increases the expression of myostatin and MAFbx in muscle. 1760 55


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