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)

Mast cell hyperplasia is observed in various inflammatory skin diseases. Although the mechanisms involved in the pathogenesis of these conditions remains largely uninvestigated, it is speculated that mediators produced in the lesional skin provide a favorable microenvironment for mast cell growth. Among the proinflammatory mediators, leukemia inhibitory factor (LIF), which shares a receptor component (gp130 subunit) with interleukin-6 (IL-6), has been identified as a mast cell growth-enhancing factor produced by cells of the keratinocyte-derived cell line (KCMH-1). In this study, we investigated the effect of four IL-6 family cytokines, IL-6, IL-11, oncostatin M (OSM) and LIF on mast cell growth in a mast cell/fibroblast co-culture system. When mouse bone marrow-derived cultured mast cells (BMMC) were maintained on a NIH/3T3 fibroblast monolayer, these cytokines induced proliferation of the mast cells, but none of the cytokines had any effect on mast cell proliferation in the absence of fibroblasts. mRNA for gp130 and receptors for the four IL-6 family cytokines were detected in NIH/3T3 fibroblasts by reverse transcriptase-mediated polymerase chain reaction. In contrast, only mRNA for the IL-11 receptor and gp130 were detected in BMMC. Tyrosine phosphorylation of gp130 was observed in NIH/3T3 fibroblasts after stimulation with all the cytokines. Some IL-6 family cytokines enhanced the production of stem cell factor (SCF), a potent mast cell growth factor, from NIH/3T3 fibroblasts, but the amount of SCF produced by NIH/3T3 fibroblasts was not paralleled by the mast cell growth-enhancement induced by the IL-6 family cytokines. When anti-SCF antibody was added with the IL-6 family cytokines in the BMMC/fibroblast coculture system, a significant effect of these cytokines remained, although the growth-enhancing activity was markedly reduced. A similar result was obtained when BMMC were prepared from W/W(V)-mice, which lack functional c-kit, in the BMMC/ fibroblast coculture system. These results suggest that IL-6 family cytokines stimulate mast cell growth by a fibroblast-dependent mechanism, and also suggest the existence of another pathway between BMMC and NIH/3T3 fibroblasts cooperating with the SCF/c-kit pathway. IL-6 family cytokines may thus contribute to mast cell hyperplasia in skin diseases.
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PMID:The IL-6 family cytokines, interleukin-6, interleukin-11, oncostatin M, and leukemia inhibitory factor, enhance mast cell growth through fibroblast-dependent pathway in mice. 1182 Jul 27

The interleukins function as intercellular hormones, possessing the ability to alter the activity of a target cell population. Interleukin-4, secreted by activated T-cells, has shown antitumor activity in vitro against multiple myelomas, lymphoma, chronic myelomonocytic leukemia, and some solid tumors. Early promising clinical studies have shown the efficacy of IL-4 in decreasing the malignant lymphocyte count and in normalizing hematologic parameters in patients with CLL and in inducing transient clinical responses in patients with non-Hodgkin's lymphoma. Interleukin-6 possesses immunomodulating properties including enhancement of NK cell activity and induction of cytotoxic T-cell activity. IL-6 has shown antitumor activity in mice injected with weakly immunogenic syngeneic tumors and has been shown to inhibit in vitro human breast carcinoma and leukemia/lymphoma proliferation through a direct tumor inhibitory effect. Clinical studies investigating the antitumor activity of IL-6 are currently in phase II clinical trials. IL-6 and IL-11 have demonstrated thrombopoietic enhancing activity in primate models and early clinical trials. These agents have a potential application in ameliorating the thrombocytopenia associated with myeloablative chemotherapy. Yet to enter clinical trials, IL-12 has been shown to enhance the lytic activity of nonspecific NK/LAK cells and appears to be more efficient than IL-2 or IFN's in enhancing NK cytotoxicity. IL-12 has also been shown to enhance specific allogeneic human CTL responses and to induce the secretion of IFN-gamma from both resting and activated T and NK cells. In summary, these interleukins are now promising agents under investigation as effective treatment strategies in the oncologic setting.
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PMID:A Review of the New Cytokines: IL-4, IL-6, IL-11, and IL-12. 1183 74

Oncostatin M (OSM) is a glycoprotein cytokine that is produced by activated T-lymphocytes, monocytes, and macrophages. In a DNA synthesis assay, OSM reduced tritiated thymidine incorporation by 53% in Calu-1 lung carcinoma cells. Radiolabeled cDNAs from untreated Calu-1 cells and 30-h OSM-treated cells were used to probe duplicate nylon membrane cDNA expression arrays. This study revealed OSM-mediated expression of mRNAs encoding tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1). Northern blot analysis showed that the steady-state level of tPA mRNA is nearly undetectable in Calu-1 cells. Exposure of these cells to OSM for 30 h increased tPA mRNA expression by 20-fold and PAI-1 mRNA expression by 5-fold. Exposure of these cells to other gp130 receptor family cytokines, including leukemia inhibitory factor (LIF), interleukin-6 (IL-6), and IL-11, do not significantly affect DNA synthesis or induction of tPA/PAI-1. Western blot studies demonstrated that OSM mediates a marked increase in secretion of the tPA protein. Secreted tPA was present in the conditioned medium almost exclusively as tPA/PAI-1 complexes. Inhibitor studies demonstrated that OSM-mediated induction of tPA and PAI-1 mRNAs is largely dependent upon activation of the MEK1/2 pathway. The JAK3/STAT3 pathway potentially serves a secondary role in these regulatory events.
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PMID:Oncostatin M induces tissue-type plasminogen activator and plasminogen activator inhibitor-1 in Calu-1 lung carcinoma cells. 1209 Jul 57

The leukemia inhibitory factor/interleukin-6 (LIF/IL-6) family of cytokines is known to play a major role in bone physiology. Although much work has focused on the regulation of bone resorption by IL-6 and related cytokines, their effects on osteoblast development and bone formation have not been as well studied. Previously, we reported that LIF inhibits, in a non-IL-6-dependent manner, osteoblast differentiation and bone nodule formation in the rat calvaria (RC) model, an effect that is antagonized by dexamethasone (Dex). The culture time-sensitive window suggested that LIF targets late preosteoblasts or early osteoblasts, and that this stage-specific effect coincided with a period of low endogenous production of LIF and IL-6. To detect potential crosstalk between members of this family, we have extended these observations by assessing the expression levels of other LIF/IL-6 cytokines (CNTF, OSM, IL-11, CT-1) and their receptors in the same RC cell model treated with or without LIF or Dex. Semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that IL-11 and its receptor, CNTF and its receptor, LIFR, and gp130 were constitutively expressed throughout the culture period. Expression of CT-1 and OSM increased with culture time - that is, with osteoblast differentiation - whereas the specific receptor for OSM (OSMR) was highly expressed at early timepoints and either plateaued or decreased thereafter. Continuous treatment with Dex (10(-8) mol/L) inhibited the endogenous production of IL-6, LIF, OSM, IL-11R, and OSMR, but had no detectable effect on the expression of IL-11, CT-1, CNTF, CNTFR, LIFR, or gp130. Finally, treatment with exogenously added LIF stimulated IL-6, LIF, LIFR, and OSMR, but had no other detectable effects. These data indicate that multiple members of the LIF/IL-6 family and their receptors are expressed in RC cell cultures, and are differentially regulated by Dex and LIF, suggesting that these cytokines play a complex and interdependent role, further modulated by glucocorticoid levels, in osteoprogenitor differentiation and bone nodule formation.
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PMID:Expression of leukemia inhibitory factor (LIF)/interleukin-6 family cytokines and receptors during in vitro osteogenesis: differential regulation by dexamethasone and LIF. 1211 Apr 37

Cytokines belonging to the so-called interleukin-6 (IL-6) or gp130 cytokine family, notably IL-6 and IL-11, are known as pro-resorptive cytokines, in that they promote osteoclastogenesis. Glucocorticoid (GC)-induced osteoporosis is admittedly the most frequent secondary osteoporosis. The pathogenesis still has many unresolved issues. Although the effects of GCs on cytokine production and recognition have been extensively studied, little is known about the effects of cytokines on GC action at the target level. We have focused on the effects of IL-6 and IL-11 on specific binding by type II GC receptors (GRs) in two human osteoblast-like cell lines (Saos-2 and MG-63) that have remarkably different constitutive expression of these cytokines and GRs as well. We have provided evidence that IL-6 upregulates GR binding sites, while IL-11 downregulates these sites, as determined by radioligand binding assay and Scatchard analysis. GR affinity (K(d)) did not change after exposure to both cytokines. A number of experiments were consistent with the view that in human osteoblast-like cells, cytokines of the IL-6 family have autocrine modulatory effects on GRalpha (GRbeta is a variant that does not bind specifically in our method). Complex effects of GCs on the system(s) of proinflammatory/anti-inflammatory cytokines and conversely of these cytokines on GC action could account for the dynamics of bone loss in patients given GCs and conceivably having high concentrations of these cytokines in the bone microenvironment.
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PMID:Interactions between glucocorticoids and cytokines in the bone microenvironment. 1211 64

Because many studies have focused on growth factors in multiple myeloma, the study of the cytokine network appears to be useful for this purpose. Interleukin-6 (IL-6) and IL-2 with their soluble receptors (IL-3, IL-4, IL-10, and IL-11) have been examined. Plasma cells may produce IL-6 by an autocrine mechanism whereas a paracrine mechanism is believed to be involved in the production of IL-6 by bone marrow stromal cells through an interaction between adhesion molecules present on myeloma plasma cells and their respective receptors that are present on bone marrow stromal cells. In addition, control over production of IL-6 may be exerted by other ILs such as IL-1beta and IL-10. Among target cells, the growth of normal and myeloma plasma cells is supported by IL-6, which also induces the differentiation of myeloma plasmablastic cells into mature plasma cells. This last action also is shared by IL-3, IL-4, and, most likely, IL-8. Evaluation of the serum level of IL-6, C reactive protein, soluble IL-6 receptor (sIL-6R), and soluble IL-2 receptor (sIL-2R), together with the activity exerted by IL-3 and IL-4 on some cellular subsets, may constitute an additional element in the differential diagnosis of borderline cases. However, the concomitant evaluation of all immunologic parameters could be more useful than the value of a single IL. Serum levels of IL-6, sIL-6R, sIL-2R, and the expression of membrane-bound IL-2 receptors, both on bone marrow plasma cells and on peripheral blood mononuclear cells, are correlated with disease activity and disease stage. In addition, IL-6 and sIL-6R serum levels are believed to be correlated with the duration of disease-free survival because a high serum level at the time of diagnosis is believed to be correlated with a short duration of survival. However, some laboratory parameters may express the same prognostic value as high beta(2) microglobulin and lactate dehydrogenase (LDH) serum levels together with a high plasma cell labeling index are correlated with disease activity. Furthermore, if the evaluation is performed at the time of diagnosis, high values of these parameters are correlated with a short disease-free survival. A correlation between laboratory parameters and the serum level of several cytokines was demonstrated. Hence, the real advantage of the prognostic evaluation of cytokines is reserved for patients who do not exhibit uniform results with regard to beta(2) microglobulin and LDH serum levels, or, better, for borderline cases. With regard to the differential diagnosis, all immunologic parameters should be evaluated concomitantly rather than separately to confer a real prognostic value to results. Furthermore, a particular relation was found between a high sIL-6R serum level and a poor response to chemotherapy, therefore suggesting the possibility of identifying in advance a subset of patients with a high risk of treatment failure, as has already been demonstrated in other hematologic malignancies.Finally, the majority of studies indicate that interferons are used mainly in the immunotherapy for multiple myeloma, whereas many clinical trials should still be required for the evaluation of the effectiveness of anti-I-L6 antibodies or antiidiotypic vaccines in reference to the eligible patients for these particular therapies.
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PMID:A review of the cytokine network in multiple myeloma: diagnostic, prognostic, and therapeutic implications. 1273 43

In hematopoiesis, cytokine levels modulate blood cell replacement, self-renewal of stem cells, and responses to disease. Feedback pathways regulating cytokine levels and targets for therapeutic intervention remain to be determined. Amino boronic dipeptides are orally bioavailable inhibitors of dipeptidyl peptidases. Here we show that the high-affinity inhibitor Val-boro-Pro (PT-100) can stimulate the growth of hematopoietic progenitor cells in vivo and can accelerate neutrophil and erythrocyte regeneration in mouse models of neutropenia and acute anemia. Hematopoietic stimulation by PT-100 correlated with increased cytokine levels in vivo. In vitro, PT-100 promoted the growth of primitive hematopoietic progenitor cells by increasing granulocyte-colony-stimulating factor (G-CSF), interleukin-6 (IL-6), and IL-11 production by bone marrow stromal cells. Two molecular targets of PT-100 are expressed by stromal cells- CD26/DPP-IV and the closely related fibroblast activation protein (FAP). Because PT-100 was active in the absence of CD26, FAP appears to be the hematopoietic target for PT-100. Interaction of PT-100 with the catalytic site seems to be required because amino-terminal acetylation of PT-100 abrogated enzyme inhibition and hematopoietic stimulation. PT-100 is a therapeutic candidate for the treatment of neutropenia and anemia. The data support increasing evidence that dipeptidyl peptidases can regulate complex biologic systems by the proteolysis of signaling peptides.
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PMID:Hematopoietic stimulation by a dipeptidyl peptidase inhibitor reveals a novel regulatory mechanism and therapeutic treatment for blood cell deficiencies. 1273 65

The molecular pathways involved in the differentiation of hematopoietic progenitors are unknown. Here we report that chemokine-mediated interactions of megakaryocyte progenitors with sinusoidal bone marrow endothelial cells (BMECs) promote thrombopoietin (TPO)-independent platelet production. Megakaryocyte-active cytokines, including interleukin-6 (IL-6) and IL-11, did not induce platelet production in thrombocytopenic, TPO-deficient (Thpo(-/-)) or TPO receptor-deficient (Mpl(-/-)) mice. In contrast, megakaryocyte-active chemokines, including stromal-derived factor-1 (SDF-1) and fibroblast growth factor-4 (FGF-4), restored thrombopoiesis in Thpo(-/-) and Mpl(-/-) mice. FGF-4 and SDF-1 enhanced vascular cell adhesion molecule-1 (VCAM-1)- and very late antigen-4 (VLA-4)-mediated localization of CXCR4(+) megakaryocyte progenitors to the vascular niche, promoting survival, maturation and platelet release. Disruption of the vascular niche or interference with megakaryocyte motility inhibited thrombopoiesis under physiological conditions and after myelosuppression. SDF-1 and FGF-4 diminished thrombocytopenia after myelosuppression. These data suggest that TPO supports progenitor cell expansion, whereas chemokine-mediated interaction of progenitors with the bone marrow vascular niche allows the progenitors to relocate to a microenvironment that is permissive and instructive for megakaryocyte maturation and thrombopoiesis. Progenitor-active chemokines offer a new strategy to restore hematopoiesis in a clinical setting.
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PMID:Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis. 1470 36

The physiological benefit of the febrile response is poorly understood. Here we show that fever-range thermal stress enhances the function of the L-selectin lymphocyte homing receptor through an interleukin-6 (IL-6)-dependent signaling mechanism. Thermal stimulation of L-selectin adhesion in vitro and in vivo is mediated by engagement of the gp130 signal-transducing chain by IL-6 and a soluble form of the IL-6 receptor-alpha (sIL-6Ralpha) binding subunit. Thermal control of adhesion is maintained in IL-6-deficient mice through a gp130-dependent compensatory mechanism mediated by IL-6-related cytokines (i.e., oncostatin M [OSM], leukemia inhibitory factor [LIF], and IL-11). Combined biochemical and pharmacological inhibitor (PD98059, U0126, SB203580, SP600125) approaches positioned MEK1/ERK1-2, but not p38 MAPK or JNK, in the IL-6/sIL-6Ralpha signaling pathway upstream of activation of L-selectin/cytoskeletal interactions and L-selectin avidity/affinity. These results highlight a role for gp130-linked IL-6/sIL-6Ralpha transsignaling in amplifying lymphocyte trafficking during febrile inflammatory responses.
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PMID:Central role of IL-6 receptor signal-transducing chain gp130 in activation of L-selectin adhesion by fever-range thermal stress. 1473 59

The aim of this study was to find out whether there was a correlationship between the concentrations of interleukin-6 (IL-6), IL-11, and IL-17 in synovial fluid and osseous changes in the condyle. The synovial fluid was obtained from 61 patients with temporomandibular joint disorders (TMD) and seven healthy volunteers (controls). The concentrations of IL-6, IL-11, and IL-17 were measured by enzyme-linked immunosorbent assay. IL-6 was detected in 43 of 59 (73%), IL-11 in 23 of 52 (44%) and IL-17 in 14 of 51 (27%) samples of synovial fluid. The concentrations of IL-6 and IL-11 in the joints with osseous changes in the condyle were significantly higher than in the joints without osseous changes (P < 0.05) and also higher than in the joints of the control group (P < 0.05). In addition, there was a correlation of concentrations between IL-6 and IL-11 (P < 0.05). These results suggest that IL-6 and IL-11 may participate in the pathogenesis of TMD and induce osseous changes in the condyle.
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PMID:Interleukin-6 family of cytokines as biochemical markers of osseous changes in the temporomandibular joint disorders. 1512 Dec 72

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