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 mitogen-activated protein (MAP) cascade leading to the activation of extracellular signal-regulated kinases 1/2 (ERK1/2) is critical for regulating myeloma cell growth; however, the relationship of ERK1/2 activity with vascular endothelial growth factor (VEGF) production and the effects of its downmodulation in myeloma cells are not elucidated. We found that the treatment with MAP/ERK kinase 1 (MEK1) inhibitors PD98059 or PD184352 produced a reduction of phosphorylated ERK1/2 (p-ERK1/2) levels in myeloma cells of more than 80% and prevented the increase of p-ERK1/2 induced by interleukin-6 (IL-6). MEK1 inhibitors also induced a significant inhibition of myeloma cell proliferation and blunted the stimulatory effect induced by IL-6. A significant inhibition of basal VEGF secretion by myeloma cells as well as a suppression of the stimulatory effect of IL-6 on VEGF was observed by either PD98059 or PD184352. Moreover, we also found that the PI3K kinase inhibitors, but not p38 MAPK inhibitors, reduced VEGF secretion by myeloma cells and increase the inhibitory effect of MEK1 inhibitors. In an 'in vitro' model of angiogenesis, we found that MEK1 inhibitors impair vessel formation induced by myeloma cells and restored by VEGF treatment, suggesting that the downmodulation of ERK1/2 activity reduces myeloma-induced angiogenesis by inhibiting VEGF secretion.
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PMID:Downmodulation of ERK protein kinase activity inhibits VEGF secretion by human myeloma cells and myeloma-induced angiogenesis. 1473 74

The interleukin-6 (IL6) family of cytokines signals through the common receptor subunit gp130, and subsequently activates Stat3, MAPK, and PI3K. Stat3 controls cell death and tissue remodeling in the mouse mammary gland during involution, which is partially induced by IL6 and LIF. However, it is not clear whether Stat3 activation is mediated solely through the gp130 pathway or also through other receptors. This question was explored in mice carrying two distinct mutations in the gp130 gene; one that resulted in the complete ablation of gp130 and one that led to the loss of Stat3 binding sites (gp130Delta/Delta). Deletion of gp130 specifically from mammary epithelium resulted in a complete loss of Stat3 activity and resistance to tissue remodeling comparable to that seen in the absence of Stat3. A less profound delay of mammary tissue remodeling was observed in gp130Delta/Delta mice. Stat3 tyrosine and serine phosphorylation was still detected in these mice suggesting that Stat3 activation could be the result of gp130 interfacing with other receptors. Experiments in primary mammary epithelial cells and transfected COS-7 cells revealed a p44/42 MAPK and EGFR-dependent Stat3 activation. Moreover, the gp130-dependent EGFR activation was independent of EGF ligands, suggesting a cytoplasmic interaction and cross-talk between these two receptors. These experiments establish that two distinct Stat3 signaling pathways emanating from gp130 are utilized in mammary tissue.
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PMID:Mammary gland remodeling depends on gp130 signaling through Stat3 and MAPK. 1529 6

Previous studies have demonstrated the in vitro and in vivo activity of CC-5013 (Revlimid), an immunomodulatory analog (IMiD) of thalidomide, in multiple myeloma (MM). In the present study, we have examined the anti-MM activity of rapamycin (Rapamune), a specific mTOR inhibitor, combined with CC-5013. Based on the Chou-Talalay method, combination indices of less than 1 were obtained for all dose ranges of CC-5013 when combined with rapamycin, suggesting strong synergism. Importantly, this combination was able to overcome drug resistance when tested against MM cell lines resistant to conventional chemotherapy. Moreover, the combination, but not rapamycin alone, was able to overcome the growth advantage conferred on MM cells by interleukin-6 (IL-6), insulin-like growth factor-1 (IGF-1), or adherence to bone marrow stromal cells (BMSCs). Combining rapamycin and CC-5013 induced apoptosis of MM cells. Differential signaling cascades, including the mitogen-activated protein kinase (MAPK) and the phosphatidylinositol 3'-kinase/Akt kinase (PI3K/Akt) pathways, were targeted by these drugs individually and in combination, suggesting the molecular mechanism by which they interfere with MM growth and survival. These studies, therefore, provide the framework for clinical evaluation of mTOR inhibitors combined with IMiDs to improve patient outcome in MM.
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PMID:Combination of the mTOR inhibitor rapamycin and CC-5013 has synergistic activity in multiple myeloma. 1531 77

Bioactive lysophospholipid, lysophosphatidic acid (LPA), is consistently raised in the ascites of patients with ovarian cancer. Interleukin-6 (IL-6) is a pleiotropic cytokine, which is assumed to be involved in ovarian carcinogenesis. However, the regulation of IL-6 in ovarian cancer remains largely unknown. To elucidate the pathogenesis of ovarian cancer, this study investigated how LPA affects IL-6 production in ovarian cancer cells. Experimental results indicated that LPA stimulates IL-6 expression in all ovarian cancer cell lines tested, but not in normal ovarian surface epithelial (NOSE) cells, owing to the lack of LPA-specific Edg4 and/or Edg7 receptors in NOSE cells. This work demonstrated that LPA transcriptionally activates IL-6 expression, which can be totally blocked by the pertussis toxin, indicating that Gi-mediated signaling is critically involved in inducing IL-6 by LPA. Pharmacological and genetic inhibition assays revealed that Gi-mediated PI3K activation phosphorylated downstream Akt and subsequently induced NF-kappaB activation causes the induction of IL-6 by LPA in SK-OV-3 cells. In summary, data presented here demonstrate that LPA is an important inducer of IL-6 and LPA-regulated IL-6 expression via a Gi/PI3K-Akt/NF-kappaB pathway in ovarian cancer cells, providing molecular therapeutic targets for treating ovarian cancer.
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PMID:Up-regulation of interleukin-6 in human ovarian cancer cell via a Gi/PI3K-Akt/NF-kappaB pathway by lysophosphatidic acid, an ovarian cancer-activating factor. 1547 96

Multiple myeloma is a clonal malignancy of plasma cells that invariably progresses to a chemoresistant state. The PI3K/Akt pathway mediates signals downstream of several growth factors involved in myeloma pathogenesis, and constitutive activation of Akt was observed in myeloma cells. We now report that a staurosporine derivative, N-benzoylated staurosporine or PKC412, induces cell death in myeloma cell lines (RPMI8226S, U266, MM1S and MM1R) with loss of mitochondrial membrane potential Delta psi m, caspase 3 and PARP cleavage. ZVAD.fmk, but not interleukin-6, rescued these cells from PKC412 effects. Upstream of the mitochondria, PKC412 inhibited Bad phosphorylation and attenuated Akt kinase activity by suppressing its phosphorylation on serine residue in its activation loop. Reduced phosphorylation of downstream Akt substrates GSK3 alpha/beta and FKHR was also noted. Stable transfection of 8226S cells with constitutively active Akt (8226S-myAkt) partially protected against PKC412 cytotoxicity. Primary myeloma cells isolated from refractory myeloma patients (n=4), were equally sensitive to PKC412 treatment. More importantly, PKC412 did not affect CFU-GM or BFU-E colony formation. In summary, our results demonstrate that PKC412 suppresses Akt kinase activation and induces apoptosis in myeloma cell lines, as well as primary resistant cells. PKC412 is an appropriate candidate for novel treatment protocols for multiple myeloma.
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PMID:N-benzoylstaurosporine (PKC412) inhibits Akt kinase inducing apoptosis in multiple myeloma cells. 1601 36

Cytokines play a central role in maintaining self-renewal in mouse embryonic stem (ES) cells through a member of the interleukin-6 type cytokine family termed leukemia inhibitory factor (LIF). LIF activates the JAK-STAT3 pathway through the class I cytokine receptor gp130, which forms a trimeric complex with LIF and the class I cytokine receptor LIF receptor beta. STAT3 has been shown to play a crucial role in self-renewal in mouse ES cells probably by induction of c-myc expression. Thus, ablation of STAT3 activation leads to differentiation. However, important connections between STAT3 and other signalling pathways have been documented. In addition, gp130 activation leads to both PI3K and Src activation. The canonical Wnt pathway is sufficient to maintain self-renewal of both human ES cells and mouse ES cells. It seems quite possible that the main pathway maintaining self-renewal in ES cells is the Wnt pathway, while the LIF-JAK-STAT3 pathway is present in mouse cells as an adaptation for sustaining self-renewal during embryonic diapause, a condition of delayed implantation in mammals. In keeping with this scenario, the Wnt pathway has been shown to elevate the level of c-myc. Thus, the two pathways seem to converge on c-myc as a common target to promote self-renewal. Whereas LIF does not seem to stimulate self-renewal in human embryonic stem cells it cannot be excluded that other cytokines are involved. The pleiotropic actions of the increasing number of cytokines and receptors signalling via JAKs, STATs and SOCS exhibit considerable redundancy, compensation and plasticity in stem cells in accordance with the view that stem cells are governed by quantitative variations in strength and duration of signalling events known from other cell types rather than qualitatively different stem cell-specific factors.
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PMID:Cytokine signalling in embryonic stem cells. 1648 Apr 48

Interleukin-6 (IL-6) is involved in angiogenesis. However, the underlying mechanisms are unknown. Using human cerebral endothelial cell (HCEC), we report for the first time that IL-6 triggers HCEC proliferation and migration in a dose-dependent manner, specifically associated with enhancement of VEGF expression, up-regulated and phosphorylated VEGF receptor-2 (KDR), and stimulated MMP-9 secretion. We investigated the signal pathway of IL-6/IL-6R responsible for KDR's regulation. Pharmacological inhibitor of PI3K failed to inhibit IL-6-mediated VEGF overexpression, while blocking ERK1/2 with PD98059 could abolish IL-6-induced KDR overexpression. Further, neutralizing endogenous VEGF attenuated KDR expression and phosphorylation, suggesting that IL-6-induced KDR activation is independent of VEGF stimulation. MMP-9 inhibitor GM6001 significantly decreases HCEC proliferation and migration (p<0.05), indicating the crucial function of MMP-9 in promoting angiogenic changes in HCECs. We conclude that IL-6 triggers VEGF-induced angiogenic activity through increasing VEGF release, up-regulates KDR expression and phosphorylation through activating ERK1/2 signaling, and stimulates MMP-9 overexpression.
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PMID:Interleukin-6 triggers human cerebral endothelial cells proliferation and migration: the role for KDR and MMP-9. 1651 57

M1 myeloid leukemic cells were used to dissect the molecular mechanisms of myeloid cell survival and apoptosis. A salient feature of M1 cells is that they respond to the physiological survival factor interleukin-6 (IL-6), yet lack the tumor suppressor gene p53. Functional wild-type activation of temperature-sensitive p53 protein (p53 val) at permissive temperature in M1-t-p53 cells results in rapid apoptosis, which is blocked by IL-6. How p53 induces M1 apoptosis and how IL-6 protects against p53-induced apoptosis are not fully understood. Here it is shown that p53-mediated apoptosis of M1 cells involves rapid activation of the proapoptotic Fas/CD95 death pathway, which activates caspases 8 and 10. Functional p53 also targets the mitochondria, causing upregulation of proapoptotic Bax, downregulation of prosurvival Bcl-2 and activation of caspase 9. IL-6 was found to protect against p53-induced apoptosis via activation of the PI3K/Akt survival pathway, which in turn counters both the Fas/CD95 and mitochondrial apoptotic pathways and activates the prosurvival transcription factor nuclear factor-kappaB (NF-kappaB). Taken together, this work supports a novel model for leukemic progression where cells that acquire the ability to produce an autocrine survival factor, such as IL-6, can bypass normal p53 surveillance function by targeting Akt, which in turn can exert effects on the regulators of apoptosis, such as the Fas/CD95 pathway, the mitochondria and NF-kappaB.
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PMID:Phosphatidylinositol 3-kinase/Akt signaling mediates interleukin-6 protection against p53-induced apoptosis in M1 myeloid leukemic cells. 1709 22

Heparin-binding EGF-like growth factor (HB-EGF) is a member of the EGF family that binds to and activates EGF receptor, and is expressed in a variety of tissues, predominantly in the lung, heart, brain and skeletal muscle. HB-EGF is known to induce vascular smooth muscle cell (VSMC) proliferation by activating PI3K-Akt and MAPK pathway. However, our preliminary data showed that Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway was also involved in HB-EGF induced VSMC proliferation. More interestingly, HB-EGF (10 ng/ml) induced a biphasic activation of STAT3 (early at 5 min and late at 60-120 min). Therefore, we tried to elucidate the underlying mechanism of this delayed STAT3 activation by HB-EGF in VSMCs. First, we examined the effect of HB-EGF on interleukin-6 (IL-6) mRNA expressions, since IL-6 have been implicated in the regulation of STAT3 activation. According to our data, HB-EGF increased transcription of IL-6, cardiotrophin-1 (CT-1), leukemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF). The secretion of IL-6 was also increased by HB-EGF. Furthermore, these HB-EGF-mediated up-regulation of IL-6 mRNA expression and secretion were inhibited by NF-kappaB inhibitor Bay117082 (2.5 microM) treatment suggesting involvement of NF-kappaB pathway. Again, the late activation of STAT3 by HB-EGF was abolished by both Bay117082 and IL-6 neutralizing antibody (1 microg/ml) indicating IL-6 is a key molecule in the delayed activation of STAT3 by HB-EGF. In addition, IL-6 neutralizing antibody inhibited both HB-EGF conditioned media induced STAT3 activation and HB-EGF induced VSMC proliferation. In conclusion, IL-6 plays an important role in the delayed activation of STAT3 and VSMC proliferation induced by HB-EGF.
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PMID:HB-EGF induces delayed STAT3 activation via NF-kappaB mediated IL-6 secretion in vascular smooth muscle cell. 1782 89

Interleukin-6 (IL-6) is secreted in great quantity in prostatic tumoral glandular tissue with a significant higher rate in hormono-refractory phase. Importance of IL-6 dependent mechanism in prostate cancer progression is well argued. IL-6 seems to be implicated in androgen receptor activation in lack of steroid ligand, apoptosis decrease and increase of invasive capacity and angiogenesis via three major signaling pathways: MAPK, STAT3 and PI3K-Akt. As AR is a key factor of prostate cancer progression, IL-6 implication in this activation underlines IL-6 importance in prostate cancer. IL-6 also induces neuroendocrine differentiation. This phenomenon received a detailed attention because it would take part in pathogenicity and progression of prostate cancer. Although complementary studies seem necessary, taking into account its strong implication in prostate cancer progression, IL-6 seems to be a new potential therapeutic target of prostate cancer.
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PMID:[Interleukin-6 implication in prostate cancer]. 1784 91


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