UNIPROT:P05231 - FACTA Search

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Query: UNIPROT:P05231 (interleukin-6)
23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During the last few years, progress has been made towards the understanding of local regulation of bone remodelling especially in relation to osteoporosis. Cytokines have shown to be powerful regulators of bone resorption and formation, though under superior control from oestrogen/testosterone, parathyroidhormone and 1,25(OH)2D3. Some of the cytokines primarily enhance osteoclastic bone resorption e.g. IL-1 (Interleukin-1), TNF (Tumor Necrosis Factor) and IL-6 (Interleukin-6), while others primarily stimulate bone formation e.g. TGF-beta (Transforming Growth Factor), IGF (Insulin-like Growth Factor) and PDGF (Platelet Derived Growth Factor). Another category has complex functions with stimulation of bone formation in vitro but stimulation of bone resorption in vivo; IFN-gamma (Interferon-gamma) belongs to this category. The bone remodelling cycle is delicately regulated, and even a slight disturbance in this regulation can cause a pathological state in the bone such as osteoporosis. This paper will try to give a survey of some of the processes that regulate bone metabolism and hopefully contribute to understanding the changes in the remodelling related to osteoporosis.
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PMID:[Cytokines and osteoporosis]. 944 61

Fatigue occurs in more than 70% of patients treated with interferon-alpha (IFN-alpha) and is the most problematic toxicity associated with IFN-based immunotherapy. Abundant evidence suggests that immune-mediated endocrine disease occurs during IFN-alpha therapy, which may contribute to the etiology of fatigue. Autoimmune thyroid disease is a well-recognized consequence of IFN-alpha therapy and may be mediated by the induction of IFN-gamma production by lymphocytes. Administration of exogenous IFN-gamma has been associated with upregulation of class II major histocompatibility antigens in the thyroid and the development of thyroiditis. Interferon-alpha also stimulates the production of interleukin-6; both interleukin-6 and IFN-gamma have specific effects on thyrocyte function. There also is evidence suggesting that IFN-alpha initiates a cytokine cascade that effects the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes, thus affecting regulation of glucocorticoid and sex steroid hormone secretion, but the clinical significance of these observations has not been established. Although endocrine disease will not explain the occurrence of fatigue symptoms in all patients, there is clear evidence that hormonal deficiency syndromes occur in a relatively large portion of patients receiving systemic IFN-alpha therapy. Most importantly, the possibility of hypothyroidism must be considered; however, diagnosis of hypothyroidism in cancer patients is complicated by the occurrence of the "sick euthyroid syndrome." Clinical recommendations for assessment and treatment of IFN-alpha-induced fatigue are offered. Most importantly, measurements of thyroid-stimulating hormone and antithyroid autoantibodies should be used to evaluate thyroid status. Acknowledging the limitations of current clinical data, adrenal- and gonadal-axis dysfunction also must be considered in patients with IFN-alpha-induced fatigue.
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PMID:Endocrine-mediated mechanisms of fatigue during treatment with interferon-alpha. 948 41

Primary effusion lymphoma (PEL) is a distinct clinicopathologic entity associated with Kaposi's sarcoma-associated herpes virus (KSHV). Several cytokines, including interleukin-6 (IL-6), basic fibroblast growth factor (bFGF), and platelet-derived growth factor (PDGF) may be important for survival of KS cells. However, little is known about the interaction of cytokines with KSHV-infected lymphocytes from PEL. Therefore, we investigated what cytokines were produced by KSHV-infected PEL cell lines (KS-1, BC-1, BC-2), what cytokine receptors were expressed by these cells, what response these cells had to selected cytokines, and what was the effect of IL-6 antisense phosphorothioated oligonucleotides. Reverse transcriptase-polymerase chain reaction (RT-PCR) and protein studies showed that these three cell lines produced IL-10, IL-6, and the receptors for IL-6. The granulocyte macrophage colony-stimulating factor (GM-CSF), IL-1beta, IL-8, IL-12, bFGF, PDGF, and c-kit transcripts were not detected in the cell lines. High levels (0.7 to 5 ng/mL/10(6) cells/48 hours) of IL-6 protein were consistently detected in supernatants of the cell lines by enzyme-linked immunosorbent assay (ELISA) tests. In clonogenic assays, interferon-alpha (IFN-alpha) and IFN-gamma suppressed the clonal growth of the PEL cells, but GM-CSF, IL-4, IL-6, IL-8, IL-10, and oncostatin M did not change it. We examined for several autocrine loops that have been suggested to occur in KS. Experiments using antisense oligonucleotides showed that the clonal growth of KS-1 and BC-1 was nearly 100% inhibited by IL-6 antisense oligonucleotides (10 micromol/L), but not at all by either oligonucleotides (</=10 micromol/L) to IL-6 sense, IL-6 scrambled, viral IL-6 (vIL-6) antisense, or IL-10 antisense. Furthermore, the IL-6 antisense oligonucleotides had no effect on two B-cell lymphoma cell lines, which were not infected with KSHV. Addition of IL-6 antibody did not inhibit clonal growth of any of the cell lines. Taken together, we have defined the cytokines and their receptors expressed on PEL cells and have found that these cells synthesized IL-6 and IL-6 receptors; interruption of this pathway by IL-6 antisense oligonucleotides specifically prevented the growth of these cells. These findings will offer potential new therapeutic strategies for PEL.
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PMID:Mechanisms of growth control of Kaposi's sarcoma-associated herpes virus-associated primary effusion lymphoma cells. 951 48

We examined the expression and activity of inducible nitric oxide synthase (iNOS) in both gamma interferon (IFN-gamma)-treated and untreated murine macrophages infected with the gram-negative bacterium Brucella suis. The bacteria were opsonized with a mouse serum containing specific antibrucella antibodies (ops-Brucella) or with a control nonimmune serum (c-Brucella). The involvement of the produced NO in the killing of intracellular B. suis was evaluated. B. suis survived and replicated within J774A.1 cells. Opsonization with specific antibodies increased the number of phagocytized bacteria but lowered their intramacrophage development. IFN-gamma enhanced the antibrucella activity of phagocytes, with this effect being greater in ops-Brucella infection. Expression of iNOS, interleukin-6, and tumor necrosis factor alpha (TNF-alpha) mRNAs was induced in both c-Brucella- and ops-Brucella-infected cells and was strongly potentiated by IFN-gamma. In contrast to that of cytokine mRNAs, iNOS mRNA expression was independent of opsonization. Similar levels of iNOS mRNAs were expressed in IFN-gamma-treated cells infected with c-Brucella or ops-Brucella; however, expression of iNOS protein and production of NO were detected only in IFN-gamma-treated cells infected with ops-Brucella. These discrepancies between iNOS mRNA and protein levels were not due to differences in TNF-alpha production. The iNOS inhibitor N omega-nitro-L-arginine methyl ester increased B. suis multiplication specifically in IFN-gamma-treated cells infected with ops-Brucella, demonstrating a microbicidal effect of the NO produced. This observation was in agreement with in vitro experiments showing that B. suis was sensitive to NO killing. Together our data indicate that in B. suis-infected murine macrophages, the posttranscriptional regulation of iNOS necessitates an additive signal triggered by macrophage Fcgamma receptors. They also support the possibility that in mice, NO favors the elimination of Brucella, providing that IFN-gamma and antibrucella antibodies are present, i.e., following expression of acquired immunity.
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PMID:Expression and bactericidal activity of nitric oxide synthase in Brucella suis-infected murine macrophages. 952 47

The potential contribution made by the inflammatory cytokines, interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) to the adjuvant activity of aluminium hydroxide gels (Alum) or Freund's complete adjuvant (FCA) was studied by comparing the immunological responses of IL-6- or TNF receptor 1- (p55; TNFR-1) deficient mice with immunocompetent control mice. While both TNFR-1- and IL-6-deficient mice primed with ovalbumin (OVA) prepared in either Alum or FCA produced similar IgG.1 responses in comparison to control mice, the pattern of T-helper type 1- (Th1) dependent IgG2a production was significantly altered. In TNFR-1-deficient mice, IgG2a responses were greater than in control mice when FCA, but not when Alum, was used as an adjuvant. Correspondingly, spleen cells from FCA-inoculated TNFR-1-deficient mice restimulated with antigen in vitro produced higher Th1 cytokine (interferon-gamma; IFN-gamma) levels with no alteration in Th2 cytokine (IL-4; IL-5, IL-6 and IL-10) production in comparison with wild-type mice. Higher levels of IgG2a were also detected in IL-6-deficient mice compared with wild-type mice following inoculation with OVA prepared in either FCA or in Alum. Furthermore, analysis of cytokine production by spleen cells revealed that both Th1 and Th2 cytokine production was higher in IL-6-deficient mice compared with control mice. As the majority of the effects of TNF-alpha are mediated via TNFR-1, we conclude that this cytokine inhibits the adjuvant activities of FCA. Furthermore, the results also imply that immunopotentiating effects of FCA or Alum adjuvant are both inhibited by IL-6.
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PMID:Neither interleukin-6 nor signalling via tumour necrosis factor receptor-1 contribute to the adjuvant activity of Alum and Freund's adjuvant. 953 17

Interferon-gamma (IFNgamma) transmits its signal through a specific cell surface receptor (IFNgammaR), which consists of a primary ligand binding alpha-chain (IFNgammaR alpha) and a signaling beta-chain (IFNgammaR beta). Recent studies identified the cytokines IFNgamma, interleukin-6 (IL-6), IL-1alpha, and tumor necrosis factor-alpha in testicular cells. Therefore, we: 1) examined the expression of IFNgammaR alpha and IFNgammaR beta subunits in freshly isolated and purified rat testicular cells; 2) examined the differential regulation of receptor components by cytokines using primary cultures of Sertoli cells; 3) identified the cell signaling pathway components of testicular IFNgammaR; and 4) characterized the functional role of testicular IFNgamma using primary Sertoli cells. We demonstrated the messenger RNAs for both chains of IFNgammaR in rat testicular cells using Northern hybridization analysis. Western blot analysis and immunocytochemistry showed that both specific IFNgammaR protein subunits were present in cultured primary Leydig and Sertoli cells prepared from the testes of immature rats. The expression of both IFNgammaR component messenger RNAs in cultured Sertoli cells was increased by its specific ligand (IFNgamma), as well as IL-1alpha and tumor necrosis factor-alpha, in both a time- and dose-dependent manner. IFNgamma-activation of the Janus (JAK) tyrosine kinases, JAK1 and JAK2 proteins, indicate that IFNgammaR, expressed in the Sertoli cell, is functional. Moreover, IFNgamma modulates the expression of interferon regulatory factor (IRF)-1 and IL-1beta converting enzyme genes in Sertoli cells. Thus, our data are suggestive of a role(s) for IFN-gamma in the regulation of distinct gene expression and cell-specific sensitivity to apoptosis in the testis.
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PMID:Identification and regulation of testicular interferon-gamma (IFNgamma) receptor subunits: IFNgamma enhances interferon regulatory factor-1 and interleukin-1beta converting enzyme expression. 956 81

The 70-kDa recombinant Candida albicans heat shock protein (CaHsp70) and its 21-kDa C-terminal and 28-kDa N-terminal fragments (CaHsp70-Cter and CaHsp70-Nter, respectively) were studied for their immunogenicity, including proinflammatory cytokine induction in vitro and in vivo, and protection in a murine model of hematogenous candidiasis. The whole protein and its two fragments were strong inducers of both antibody (Ab; immunoglobulin G1 [IgG1] and IgG2b were the prevalent isotypes) and cell-mediated immunity (CMI) responses in mice. CaHsp70 preparations were also recognized as CMI targets by peripheral blood mononuclear cells of healthy human subjects. Inoculation of CaHsp70 preparations into immunized mice induced rapid production of interleukin-6 (IL-6) and tumor necrosis factor alpha, peaking at 2 to 5 h and declining within 24 h. CaHsp70 and CaHsp70-Cter also induced gamma interferon (IFN-gamma), IL-12, and IL-10 but not IL-4 production by CD4+ lymphocytes cocultured with splenic accessory cells from nonimmunized mice. In particular, the production of IFN-gamma was equal if not superior to that induced in the same cells by whole, heat-inactivated fungal cells or the mitogenic lectin concanavalin A. In immunized mice, however, IL-4 but not IL-12 was produced in addition to IFN-gamma upon in vitro stimulation of CD4+ cells with CaHsp70 and CaHsp70-Cter. These animals showed a decreased median survival time compared to nonimmunized mice, and their mortality was strictly associated with organ invasion by fungal hyphae. Their enhanced susceptibility was attributable to the immunization state, as it did not occur in congenitally athymic nude mice, which were unable to raise either Ab or CMI responses to CaHsp70 preparations. Together, our data demonstrate the elevated immunogenicity of CaHsp70, with which, however, no protection against but rather some enhancement of Candida infection seemed to occur in the mouse model used.
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PMID:A 70-kilodalton recombinant heat shock protein of Candida albicans is highly immunogenic and enhances systemic murine candidiasis. 957 2

During infection and injury a series of metabolic events are activated that leads to a state of negative nitrogen balance and significant loss of lean body mass. This process is characterized by marked anorexia, net whole body protein breakdown, and liver anabolism. This host response initially is beneficial to the body because it helps it to fight disease and enhance healing. However, if such imbalance is maintained for long periods, it will invariably produce significant loss of lean body mass that may lead to a series of untoward clinical events. The role of the proximate cytokines, tumor necrosis factor (TNF), interleukin-1 (IL-1), and interleukin-6 (IL-6) as well as glucocorticoids as important mediators of many pathophysiological manifestations of infection and injury has been studied extensively. However, the involvement of other mediators, at least in skeletal muscle proteolysis during sepsis has been hypothesized, because blockade of glucocorticoids, TNF, IL-1, and IL-6 reduces but does not normalize protein breakdown rates nor does the direct application of these mediators to skeletal muscle in vitro enhance proteolysis. Furthermore other studies have suggested that the lymphokine, interferon-gamma (IFN-gamma, type II interferon or immune interferon), produces fever and enhances thermogenesis, body weight loss, and skeletal muscle depletion in rodents in a manner similar to that seen with TNF and IL-1. Cytokines appear to be major components of the host metabolic response during infection and injury. However, neither all the cytokines involved nor the exact mechanisms underlying their metabolic effects are completely understood. The regulation of muscle protein synthesis and breakdown, which largely determines the development of cachexia, appears to depend on the delicate balance between a number of regulatory substances including cytokines, glucocorticoids, catecholamines, insulin, and insulin-like growth factors.
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PMID:The role of cytokines in the catabolic consequences of infection and injury. 1008 3

The aim of the present study was to further characterize the role of alveolar macrophages (AM) in acute human lung inflammation by evaluating their capacity to produce pro-inflammatory cytokines such as tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-8. Patients with severe community-acquired pneumonia (CAP; n=12) and healthy volunteers (n=10) underwent bronchoalveolar lavage (BAL). AM were separated to high purity (>96%) using fluorescence-activated cell sorting. We determined the TNF-alpha, IL-6 and IL-8 cytokine gene expression in AM ex vivo using semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR). Moreover, we measured in vitro unstimulated, lipopolysaccharide (LPS)- and LPS/interferon-gamma inducible TNF-alpha, IL-6 and IL-8 cytokine release and evaluated samples of BAL fluids for the same pro-inflammatory cytokines using an enzyme-linked immunosorbent assay (ELISA). We found increased TNF-alpha, IL-6 and IL-8 messenger ribonucleic acid (mRNA) levels in AM from CAP patients that were significantly elevated only for IL-8. When challenged with endotoxin in vitro, AM obtained from CAP patients showed a strongly reduced potential to release TNF-alpha and IL-6 compared to healthy controls, whereas IL-8 secretion did not differ significantly between groups. Moreover, stimulation of AM from CAP patients with LPS plus IFN-gamma augmented TNF-alpha and IL-6 cytokine release to near normal levels. Interestingly, no TNF-alpha protein was measured in BAL samples from CAP patients, whereas IL-6 and IL-8 protein levels were found to be significantly increased. Together, highly purified alveolar macrophages from community-acquired pneumonia patients show relatively low ex vivo tumour necrosis factor-alpha and interleukin-6 but not interleukin-8 messenger ribonucleic acid levels that are associated with a decreased pro-inflammatory cytokine release in vitro which, however, can be restored by concurrent interferon-gamma stimulation.
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PMID:Expression of pro-inflammatory cytokines by flow-sorted alveolar macrophages in severe pneumonia. 959 98

Gab1 has structural similarities with Drosophila DOS (daughter of sevenless), which is a substrate of the protein tyrosine phosphatase Corkscrew. Both Gab1 and DOS have a pleckstrin homology domain and tyrosine residues, potential binding sites for various SH2 domain-containing adapter molecules when they are phosphorylated. We found that Gab1 was tyrosine phosphorylated in response to various cytokines, such as interleukin-6 (IL-6), IL-3, alpha interferon (IFN-alpha), and IFN-gamma. Upon the stimulation of IL-6 or IL-3, Gab1 was found to form a complex with phosphatidylinositol (PI)-3 kinase and SHP-2, a homolog of Corkscrew. Mutational analysis of gp130, the common subunit of IL-6 family cytokine receptors, revealed that neither tyrosine residues of gp130 nor its carboxy terminus was required for tyrosine phosphorylation of Gab1. Expression of Gab1 enhanced gp130-dependent mitogen-activated protein (MAP) kinase ERK2 activation. A mutation of tyrosine 759, the SHP-2 binding site of gp130, abrogated the interactions of Gab1 with SHP-2 and PI-3 kinase as well as ERK2 activation. Furthermore, ERK2 activation was inhibited by a dominant negative p85 PI-3 kinase, wortmannin, or a dominant negative Ras. These observations suggest that Gab1 acts as an adapter molecule in transmitting signals to ERK MAP kinase for the cytokine receptor gp130 and that SHP-2, PI-3 kinase, and Ras are involved in Gab1-mediated ERK activation.
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PMID:Gab1 acts as an adapter molecule linking the cytokine receptor gp130 to ERK mitogen-activated protein kinase. 963 95

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