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

Many members of the cytokine receptor superfamily initiate intracellular signaling by activating members of the Jak family of tyrosine kinases. Activation of the same Jaks by multiple cytokines raises the question of how these cytokines activate distinct intracellular signaling pathways. Selection of particular substrates--the transcriptional activator Stat3 and protein tyrosine phosphatase PTP1D--that characterize responses to the ciliary neurotrophic factor-interleukin-6 cytokine family depended not on which Jak was activated, but was instead determined by specific tyrosine-based motifs in the receptor components--gp130 and LIFR--shared by these cytokines. Further, these tyrosine-based motifs were modular, because addition of a Stat3-specifying motif to another cytokine receptor, that for erythropoietin, caused it to activate Stat3 in a ligand-dependent fashion.
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PMID:Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors. 787 33

The JAK2 tyrosine kinase is known to associate with the receptors for growth hormone (GH) and erythropoietin (EPO) and with the interleukin-6 receptor signal transducing protein, gp130. Here we demonstrate that chimeric cytokine receptors which contain the cytoplasmic domain of the receptors for GH and EPO or for gp130 can form complexes with JAK2 when transiently co-expressed in HeLa cells. Mutational analyses of chimeras for the the GH and EPO receptors and gp130 demonstrated that box 1, a motif critical for cytokine receptor signal transduction, was required for the association of JAK2. Although JAK2 was capable of associating with all three of the chimeras, JAK1 co-precipitated only with the gp130 chimera. Association of JAK1 and JAK2 with cytokine receptor proteins, therefore, requires the highly conserved box 1 domain, but other sequences within the receptor proteins may influence the specificity of JAK binding. Mutational analysis of JAK2 revealed that multiple or complex protein sequences within JAK2 are required for association with cytokine receptors.
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PMID:The conserved box 1 motif of cytokine receptors is required for association with JAK kinases. 789 87

Traditional diagnostic criteria for primary thrombocythaemia (PT) remain essentially negative, aiming to exclude other myeloproliferative disorders and causes of reactive thrombocytosis (RT). It would be useful to have positive markers. We have examined several parameters to see how well they discriminate between PT and RT. Three groups of patients were studied: new, untreated PT (17), treated PT (12) and RT (17). Data consisted of: ESR, plasma fibrinogen, factor VIIIC, von Willebrand factor antigen (vWF:Ag), PDW, platelet nucleotide ratio (ATP:ADP) serum erythropoietin (Epo), ristocetin cofactor (vWF:RiCoF), multimeric structure of vWF, interleukin-6, evidence of clinical ischaemia and erythroid colony formation. Erythroid colonies were assayed in a serum-free system with the addition of Epo, IL3 or alpha-IFN to produce a discriminant function (DF) successfully used in the diagnosis of primary polycythaemia in an earlier study. Acute phase reactants (ESR, fibrinogen, VIIIC, vWF:Ag) and IL6 were the best discriminants, while PDW and serum Epo were less so. ATP:ADP and clinical ischaemia were nondiscriminatory in this study. Reduction in vWF:RiCof and in high molecular weight multimers were clearly associated with PT. Endogenous erythroid colonies were nondiscriminatory, but half the PT group and only one patient in the RT group obtained a DF suggestive of myeloproliferative disorder. Judicious use of a battery of tests may provide support for diagnosis of PT in difficult cases.
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PMID:Primary thrombocythaemia: a composite approach to diagnosis. 795 22

1. Serum levels of erythropoietin and the immune parameters tumour necrosis factor-alpha, soluble interleukin-2 receptor, interleukin-2, interleukin-6 and interferon-gamma were measured in patients with rheumatoid arthritis. 2. Out of 69 patients, 44 had anaemia with serum haemoglobin concentrations of 10.8 (SD 1.2) g/dl. In these patients erythropoietin levels were significantly higher than in non-anaemic patients [51.97 (SD 23.9) versus 26.06 (SD 11.9) m-units/ml; P < 0.0001; control patients: 18.1 (SD 13.8) m-units/ml]. Mean soluble interleukin-2 receptor activity was elevated in all patients with rheumatoid arthritis [1324 (SD 715) units/ml; control patients: 480 (SD 75) units/ml; P < 0.001] and was significantly higher in the anaemic group than in the non-anaemic group [1562 (SD 662) versus 696 (SD 402) units/ml; P < 0.0001]. The serum activity of soluble interleukin-2 receptor showed an inverse correlation with haemoglobin (r = 0.79; P < 0.0001) and a positive correlation with erythropoietin (r = 0.70, P < 0.0001). 3. Elevated serum tumour necrosis factor-alpha levels were found in 19 anaemic patients [20.6 (SD 9.1) pg/ml]. Concentrations of tumour necrosis factor-alpha in serum showed an inverse correlation with haemoglobin (r = 0.57, P < 0.001) and a positive correlation with erythropoietin (r = 0.46, P < 0.05). Interleukin-6 was detected in seven anaemic patients [21 (SD 14) pg/ml] and interleukin-2 activity in three anaemic patients (12, 16 and 14 units/ml, respectively). Interferon-gamma was not detected in any of the patients investigated.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Impaired erythropoietin responsiveness in anaemic rheumatoid arthritis patients: potential relation to immune mechanisms. 803 17

To define the toxicity profile of recombinant human interleukin-6 (rhIL-6) and to study its effect on hematopoiesis, biochemical parameters and other cytokines, rhIL-6 was administered in a phase I-II study to 20 patients with breast carcinoma or nonsmall cell lung cancer. RhIL-6 doses were 0.5, 1.0, 2.5, 5.0, 10, and 20 micrograms/kg/d, with at least three patients per dose level. RhIL-6 was administered 24 hours by continuous intravenous infusion followed by subcutaneous (SC) administration for 6 days, partly on an outpatient basis. RhIL-6-related side effects were fever, headache, myalgia, and local erythema. Starting at 2.5 micrograms/kg/d, these side effects were compounded by nausea, reversible increase in liver enzymes, and anemia. Flu-like symptoms were controllable up to and including 10 micrograms rhIL-6/kg/d with acetaminophen. RhIL-6 increased platelet counts with a decrease in mean platelet volume and increased leukocytes caused by neutrophil, monocyte, and lymphocyte increase, with an increase in T cells and natural killer cells at 1.0 and 2.5 micrograms rhIL-6/kg/d. The reversible anemia was characterized by a decrease in serum iron, and an increase in ferritin and erythropoietin without reticulocytosis. RhIL-6 reduced total cholesterol levels and a dose-related increase of C-reactive protein and serum amyloid A plasma levels was observed. Serum IL-6 levels were increased, especially at 10 and 20 micrograms/kg/d, whereas no change in IL-1 beta and tumor necrosis factor alpha levels was observed. RhIL-6 can be administered with controllable side effects in this setting, up to and including a SC dose of 10 micrograms/kg/d on an outpatient basis, and has a promising stimulating effect on leukopoiesis and thrombopoiesis.
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PMID:Effects of recombinant human interleukin-6 in cancer patients: a phase I-II study. 806 39

Intestinal blood loss as well as chronic inflammation are regarded as the most important mechanisms in the pathogenesis of anemia in Crohn's disease. In addition, cytokines such as interleukin-6 can suppress erythropoietin production. This study was performed to investigate the importance of iron status, inflammatory activity, and endogenous erythropoietin concentrations for the development of anemia in Crohn's disease. In 49 consecutive patients with Crohn's disease, hemoglobin, inflammatory activity (Crohn's disease activity index, C-reactive protein, alpha 1-acid glycoprotein), iron status (serum iron, transferrin, transferrin saturation, ferritin), and serum erythropoietin levels were studied. Anemic (Hb < 12.0 g/dl; N = 16) vs nonanemic patients (Hb > or = 12 g/dl; N = 33) showed reduced iron compartments (eg, ferritin 28.7 +/- 12.9 micrograms/liter vs 63.2 +/- 15.0 micrograms/liter, transferrin saturation 6.2 +/- 1.4% vs 11.5 +/- 1.3%, P < 0.01) but no differences in inflammatory activity. An inverse correlation between erythropoietin and hemoglobin concentrations was found (r = -0.62; P < 0.001), but the increase in erythropoietin levels was inadequate to the degree of anemia. There was no correlation between erythropoietin and interleukin-6 serum levels. Four of five anemic patients with hemoglobin below 10.5 g/dl and erythropoietin levels within the normal range were treated with parenteral iron (200 mg iron saccharate in 250 ml NaCl, weekly, intravenously). Two of them additionally received recombinant human erythropoietin (150 units/kg, 3x weekly, subcutaneously). After five weeks all patients had a marked increase in hemoglobin. However, the mean increase in erythropoietin-treated patients was 5.0 g/dl compared to 2.0 g/dl in the patients with iron therapy only.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Anemia in Crohn's disease. Importance of inadequate erythropoietin production and iron deficiency. 808 99

Cellular turnover of the hematopoietic system is supported by a small population of cells termed hematopoietic stem cells. Stem cells are capable of self-renewal and differentiation into individual lymphomyeloid lineages. Available evidence indicates that the decision of a stem cell to self-renew or differentiate and the decision of a multipotential progenitor to select a lineage pathway during differentiation (commitment) are intrinsic to the progenitors and are stochastic in nature. In contrast, proliferative kinetics of the progenitors, namely, survival and expansion of the progenitors, appear to be controlled by a number of interacting cytokines. Whereas proliferation and maturation of committed progenitors are controlled by late-acting factors such as erythropoietin, macrophage colony-stimulating factor, granulocyte colony-stimulating factor, and interleukin-5, progenitors at earlier stages of development are controlled by a group of several overlapping cytokines. Interleukin-3, granulocyte/macrophage colony-stimulating factor, and interleukin-4 regulate proliferation of multipotential progenitors only after they are triggered to exit from dormancy state. Triggering of cycling of dormant primitive progenitors and proliferation of lymphohemopoietic primitive progenitors appear to require interactions of early acting cytokines including interleukin-6, granulocyte colony-stimulating factor, interleukin-11, interleukin-12, leukemia inhibitory factor, and steel factor.
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PMID:Hematopoiesis. 808 74

The stimulation of platelets production by human hemopoietic growth factors, became an interesting alternative in the treatment of thrombocytopenic patients. Because the lineage specific Colony Stimulating Factor of Megakaryocytes (CSF-Meg) has not yet been discovered, the aim of our study was to compare the stimulatory potential of different hemopoietic growth factors influencing megakaryocytic colony formation in vitro. According to our results the best strategy to stimulate human megakaryocytopoiesis in vivo seems to be simultaneous or sequential use of the mixture of several cytokines including: interleukin-3, interleukin-6, erythropoietin or kit ligand. The best stimulatory effect we have obtained however, using recently developed by molecular biology means recombinant fusion protein composed of joined by peptide bridge interleukin-3 and erythropoietin molecules. The data presented in this paper, could find application in the near future by elaborating more effective clinical protocols for treatment of thrombocytopenia using hemopoietic growth factors.
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PMID:[Stimulation of human megakaryopoiesis in vitro with different growth factors. Potential clinical applications]. 808 12

Cytokine levels of interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta), interleukin-3 (IL-3), interleukin-6 (IL-6), erythropoietin (EPO) and tumor necrosis factor alpha (TNF alpha) in bone marrow of Wistar rat were measured with immunofluorescent assay. The levels of IL-1 alpha, IL-1 beta, IL-3, IL-6 and EPO were high in young (4 weeks old), and gradually decreased thereafter. In contrast, TNF alpha level in bone marrow was low by 18 weeks old and high at 26 and 52 weeks old. These results indicated that age-associated changes of bone marrow cell composition in rat are well correlated with the levels of cytokine related to bone marrow cell differentiation.
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PMID:[Age-associated changes of cytokine levels in bone marrow of Wistar rat]. 825 48

The extended cytoplasmic processes from megakaryocytes (MK) are believed to be structural intermediates between MK and platelets. We could observe differentiation of purified rat CFU-MK toward mature MK to form extended cytoplasmic processes. Recombinant rat interleukin-3 (IL-3), human erythropoietin (Epo), and human interleukin-6 (IL-6) each was able to stimulate process formation although they varied somewhat in their potential. Electron microscopic observations showed that these processes were very similar to those from mature MK so far reported. The combination of IL-6 with IL-3 or Epo synergistically increased the number of MK forming processes without further increase in the number of total MK formed in the presence of IL-3 or Epo alone. In addition, IL-6 significantly increased the megakaryocytic diameter and DNA content of MK induced by IL-3 or Epo and shortened the MK transit time to hasten the process formation of MK. These findings suggest that IL-6 promotes further maturity in both the cytoplasm and ploidy of MK to form extended cytoplasmic processes. The ability of these factors to generate the process formation in vitro may be related to their thrombopoietic effects in vivo.
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PMID:Growth factor-induced process formation of megakaryocytes derived from CFU-MK. 828 May 99


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