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)

The characteristics of soluble interleukin-6 receptor (sIL-6R) in murine sera were examined. To investigate a relationship between serum sIL-6R level and autoimmune diseases, quantitative analysis of serum sIL-6R in MRL/lpr mice was performed by an enzyme-linked immunosorbent assay. The serum sIL-6R level in MRL/lpr mice of both sexes was below the detection limit (< 1.0 ng/ml) at 8 weeks of age, but it increased in accordance with age and reached 42 +/- 9.3 ng/ml in female and 31 +/- 13 ng/ml in male mice at 30 weeks of age. In MRL/+ mice, although an age-associated increase in serum sIL-6R level was observed, it was much less extensive than that in MRL/lpr mice. Elevated serum sIL-6R level at the age of 30 weeks was observed in female and male (NZB x NZW)F1 mice (32 +/- 10 ng/ml and 17 +/- 5.0 ng/ml, respectively), and male BXSB/Mpj Yaa mice (42 +/- 18 ng/ml), suggesting that elevated serum sIL-6R in aged mice is one of the characteristics of autoimmune-prone mice. Quantitative analysis of serum IL-6 in MRL/lpr revealed that the serum sIL-6R level correlated well with the serum IL-6 level. We also showed that sIL-6R in the sera from MRL/lpr mice could mediate the IL-6 functions through the IL-6 signal-transducing receptor component gp130, suggesting that elevated production of sIL-6R may partly contribute to development of autoimmune disease in MRL/lpr mice.
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PMID:Serum soluble interleukin-6 receptor in MRL/lpr mice is elevated with age and mediates the interleukin-6 signal. 847 2

The biological functions of interleukin-6 (IL-6) are mediated through a signal-transducing component of the IL-6 receptor, gp130, which is associated with the ligand-occupied IL-6 receptor (IL-6R) protein. Binding of IL-6 to IL-6R induced disulfide-linked homodimerization of gp130. Tyrosine kinase activity was associated with dimerized but not monomeric gp130 protein. Substitution of serine for proline residues 656 and 658 in the cytoplasmic motif abolished tyrosine kinase activation and cellular responses but not homodimerization of gp130. The IL-6-induced gp130 homodimer appears to be similar in function to the heterodimer formed between the leukemia inhibitory factor (LIF) receptor (LIFR) and gp130 in response to the LIF or ciliary neurotrophic factor (CNTF). Thus, a general first step in IL-6-related cytokine signaling may be the dimerization of signal-transducing molecules and activation of associated tyrosine kinases.
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PMID:IL-6-induced homodimerization of gp130 and associated activation of a tyrosine kinase. 851 89

The helical cytokine interleukin-6 (IL-6) assembles a multiprotein receptor complex. The starting event in the activation of intracellular signaling is the binding of the IL-6/IL-6R alpha subcomplex to two gp130 chains. The homodimerization of gp130 is triggered by two distinct and independent regions of IL-6 called sites 2 and 3. Several IL-6 antagonists have been obtained that affect signaling, but not IL-6 IL-6R alpha subcomplex formation. In this paper, we analyze in detail the impact of these antagonists on gp130 binding and dimerization and show that each signaling variant affects gp130 dimerization in vitro and that biological activity on cells decreases in precise parallel to the decrease in gp130 dimerization in vitro. All IL-6 antagonists can be classified into two groups, mapping at either site 2 or 3 in correspondence to their mode of interaction with gp130. We found that site 3 is a large region, which includes residues at the beginning of helix D spatially flanked by residues in the putative AB loop and located at one extremity of the cytokine 4-helix bundle. Interestingly, in leukemia inhibitory factor, another cytokine that signals through gp130, site 3, is topologically conserved but has evolved to bind leukemia inhibitory factor receptor.
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PMID:Definition of a composite binding site for gp130 in human interleukin-6. 853 91

Oligonucleotide primers for human interleukin-6 (IL-6) that bracketed the entire coding region of the gene were used in reverse transciptase-polymerase chain reaction (RT-PCR) studies to examine lL-6 expression in peripheral blood mononuclear cells (PBMC). In addition to the predicted 0.64-kb RT-PCR product, a second 0.45-kb product was observed. Cloning and dideoxy sequence analysis of this product revealed evidence for an alternatively spliced lL-6 transcript lacking exon II. Further RT-PCR analysis using forward primers ending at or one base before the exon I donor splice site again yielded both products. Additional primers were designed and successfully used to selectively distinguish the two forms of IL-6 transcript. Both transcripts were prominent in peripheral blood monocytes and lymphocytes, whereas only the 0.64-kb, full-length transcript was prominent in the lL-6-producing 5637 (human bladder carcinoma) cell line. Northern analysis revealed, in addition to the predominant 1.3-kb transcript, several minor transcripts at 1.9 to 4.8 kb that hybridized with the alternatively spliced cDNA probe but not with an exon II probe. Western analysis revealed lL-6 polypeptides of predicted size (26 to 29 kD) in culture medium from PBMC, while showing an immunoreactive band at 17 kD in cell lysates. These findings suggest the existence of an alternatively spliced form of lL-6 mRNA, which would encode for a polypeptide missing the gp130 interactive (signal-transducing) domain contained in exon II while retaining the lL-6 receptor (p80) domain. Such a molecule could in theory function as a natural antagonist of lL-6, as it would be expected to bind to the IL-6 receptor but not lead to signal transduction.
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PMID:Detection and analysis of an alternatively spliced isoform of interleukin-6 mRNA in peripheral blood mononuclear cells. 854 46

Interleukin-6 (IL-6)/IL-6 receptor (IL-6R) plays a major role in autocrine/paracrine growth regulation of myeloma cells. We investigated the effect of dexamethasone and all-trans retinoic acid, previously shown to modulate IL-6/IL-6R, on the in vitro growth of a human myeloma cell line, OPM-2. Both agents inhibited the clonogenic growth and 3H-thymidine incorporation in a concentration-dependent fashion. Isobologram and median effect analysis showed a strong synergy between these two agents with a combination index in the range of 0.2 to 0.6. Both agents decreased the labeling index and the cell fraction in S and G2/M phases, suggesting a block in G1-S phase transition. The clonogenic growth was stimulated by exogenous IL-6 and was inhibited by monoclonal antibody to IL-6, suggesting an autocrine function of IL-6. The effect of dexamethasone but not all-trans retinoic acid was completely reversed by exogenous IL-6. Dexamethasone increased, while all-trans retinoic acid reduced, IL-6R but not gp130 mRNA expression. Their combination caused a net reduction in IL-6R mRNA. Cellular IL-6R density was altered correspondingly without changes in the binding affinity. IL-6 mRNA expression was reduced by dexamethasone and the combination, but was not affected by retinoic acid alone. However, IL-6 secretion into culture supernatant was abolished by both agents. A survey of 4 additional human myeloma cells showed that 1 was sensitive to both, 1 was sensitive to one agent only, and 2 were resistant to both. The study demonstrates the possibility of regulating myeloma cell growth through modulation of IL-6/IL-6R autocrine/paracrine loop and the principle of achieving a synergistic effect by blocking this loop at multiple sites.
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PMID:Inhibition of myeloma cell growth by dexamethasone and all-trans retinoic acid: synergy through modulation of interleukin-6 autocrine loop at multiple sites. 854 58

In order to be prepared for implantation, human endometrium undergoes a predictable series of proliferative and secretory changes. Cytokines play an important role in regulation of these changes. Therefore, in this study, we immunolocalized the cytokine, interleukin-6 (IL-6), its receptor and the signal transducer gp130 in human endometrium throughout the menstrual cycle. During the entire menstrual cycle, the IL-6 receptor and gp130 were found primarily in the endometrial glands and to a lesser extent in the stroma. The immunoreactivity of these proteins did not change in endometrial cells during the entire menstrual cycle with an exception of reduced immunoreactivity of gp130 in endometrial glands during menstrual phase. Immunostaining showed that immunoreactive IL-6 was weakly expressed in human endometrium during the proliferative phase. Strong immunoreactivity for IL-6 appeared in endometrium during the putative 'implantation window'. Expression was by far most pronounced both in the glandular and surface epithelial cells. The amount of immunoreactive IL-6 in the epithelium progressively increased during the secretory/menstrual phases. During the late secretory phase, only stromal cells in the upper functionalis exhibited immunoreactivity for IL-6. Western blot analysis corroborated the immunohistochemical data. Human endometrial IL-6 consisted of a protein with an apparent mobility of 26 kDa. The immunoreactive band of IL-6 was weak in the proliferative phase. The expression of this protein increased progressively during the secretory/menstrual phases. The findings show a cell-specific pattern of distribution for immunoreactive IL-6 in human endometrium. The menstrual cycle-dependent expression of IL-6 suggests that this cytokine may play a role in changes in endometrium that prepare this tissue for implantation and menstrual shedding.
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PMID:Progressive rise in the expression of interleukin-6 in human endometrium during menstrual cycle is initiated during the implantation window. 856 15

The functional receptor complexes assembled in response to interleukin-6 and -11 (IL-6 and IL-11), leukemia inhibitory factor (LIF), oncostatin M (OSM), and ciliary neurotrophic factor (CNTF), all involve the signal transducer gp130: IL-6 and IL-11 induce homodimerization of gp130, while the rest heterodimerize gp130 with other gp130-related beta subunits. Some of these cytokines (IL-6, IL-11, and CNTF) also require a specificity-determining alpha subunit not directly involved in signaling. We have searched for functional receptor complexes for these cytokines in cells of the bone marrow stromal/osteoblastic lineage, using tyrosine phosphorylation of the beta subunits as a detection assay. Collectively, murine calvaria cells, bone marrow-derived murine cell lines (+/+LDA11 and MBA13.2), as well as murine (MC3T3-E1) and human (MG-63) osteoblast-like cell lines displayed all the previously recognized alpha and beta subunits of this family of receptors. However, individual cell types had different constellations of alpha and beta subunits. In addition and in difference to the other cell types examined, MC3T3-E1 cells expressed a heretofore unrecognized form of gp130; and MG-63 displayed an alternative form (type II) of the OSM receptor. These findings establish that stromal/osteoblastic cells are targets for the actions of all the members of the cytokine subfamily that shares the gp130 signal transducer; and suggest that different receptor repertoires may be expressed at different stages of differentiation of this lineage.
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PMID:Detection of receptors for interleukin-6, interleukin-11, leukemia inhibitory factor, oncostatin M, and ciliary neurotrophic factor in bone marrow stromal/osteoblastic cells. 856 64

Using polymerase chain reaction, interleukin-6 (IL-6) cDNA fragments from harbor seal (Phoca vitulina), killer whale (Orcinus orca), and Southern sea otter (Enhydra lutris nereis) were cloned and sequenced. For all three species, a continuous open reading frame encoding 203 residues for harbor seal, 199 residues for killer whale, and 201 residues for sea otter with stop codons located at analogous positions were identified. These fragments correspond to nucleotides 71 - 753 of the human IL-6 transcript and represent 96% of the complete coding nucleotides. Comparison of these marine mammal sequences with other published mammalian IL-6 cDNA demonstrated that both harbor seal and sea otter IL-6 had most similarity to that of other terrestrial carnivores (Mustelidae and Canidae), while killer whale had highest identity with ruminants (Bovidae and Ovidae). Among the three marine mammal species characterized, as well as cDNA sequences from nine other species, 40 invariant amino acids, including a number of residues situated at the putative gp80 and gp130 receptor binding sites, were identified. The presence of invariant amino acids within the receptor-binding portion of IL-6 for twelve different species suggests these positions are essential for biological activity of IL-6 and, moreover, likely account for the cross-reactivity among different mammalian IL-6-like activities in mouse bioassays. An additional significant finding was the presence of several variant residues only within the mouse putative IL-6 receptor binding region, which may account for observations of restricted cross-reactivity of mouse IL-6-like activity in human bioassays. Together, these findings provide insights into the evolution of the mammalian IL-6 gene and additional valuable information regarding amino acid residues essential for the biological activity of mammalian IL-6.
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PMID:Molecular cloning and sequencing of interleukin 6 cDNA fragments from the harbor seal (Phoca vitulina), killer whale (Orcinus orca), and Southern sea otter (Enhydra lutris nereis). 857 17

Five cytokines activate the gp130 IL-6 transducer: ciliary neurotrophic factor, interleukin-6, interleukin-11, leukemia inhibitory factor and oncostatin M. Human plasmacytoma cell lines, completely dependent on the addition of one of these five cytokines for their growth, were used to obtain anti-gp130 monoclonal antibodies specifically inhibiting one of these five cytokines without affecting the biological activity of the others. These antibodies should improve our understanding of the interaction of gp130 transducer using cytokines with gp130 transducer and facilitate the design of new cytokine inhibitors.
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PMID:Anti-gp130 transducer monoclonal antibodies specifically inhibiting ciliary neurotrophic factor, interleukin-6, interleukin-11, leukemia inhibitory factor or oncostatin M. 860 8

Interleukin-6 (IL-6) induces growth arrest and macrophage differentiation through its receptor in a murine myeloid leukaemic cell line, M1, although it is largely unknown how the IL-6 receptor generates these signals. By using chimeric receptors consisting of the extracellular domain of growth hormone receptor and the transmembrane and cytoplasmic domain of gp130 with progressive C-terminal truncations, we showed that the membrane-proximal 133, but not 108, amino acids of gp130 could generate the signals for growth arrest, macrophage differentiation, down-regulation of c-myc and c-myb, induction of junB and IRF1 and Stat3 activation. Mutational analysis of this region showed that the tyrosine residue with the YXXQ motif was critical not only for Stat3 activation but also for growth arrest and differentiation, accompanied by down-regulation of c-myc and c-myb and immediate early induction of junB and IRF1. The tight correlation between Stat3 activation and other IL-6 functions was further observed in the context of the full-length cytoplasmic region of gp130. The result suggest that Stat3 plays an essential role in the signals for growth arrest and differentiation.
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PMID:Differentiation and growth arrest signals are generated through the cytoplasmic region of gp130 that is essential for Stat3 activation. 861 79


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