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

Mitogen-activated protein (MAP) kinases stimulated by phorbol 13-myristate 12-acetate (PMA) have been shown to inhibit interleukin-6-induced activation of STAT3 (Sengupta, T. K., Talbot, E. S., Scherle, P. A., and Ivashkiv, L. B. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 11107-11112). In the present study we demonstrate that in addition to STAT3, also tyrosine phosphorylation of STAT1, signal transducer gp130, and phosphotyrosine-phosphatase SHP2 underlies negative regulation by MAP kinases. Stimulation of Erks by basic fibroblast growth factor or a constitutively active mutant of Raf also led to down-regulation of STAT activity. Using chimeric receptor mutants we show that tyrosine 759 of glycoprotein 130 is crucial for the inhibitory effect of MAP kinases. Inhibition is also dependent on gene transcription and translation indicating that newly synthesized proteins are involved. Both PMA and basic fibroblast growth factor rapidly stimulate mRNA expression of the suppressor of cytokine signaling-3 (SOCS-3) and this induction is strongly reduced by an inhibitor of MAP kinase activation. Together with recent results demonstrating that SOCS-3 can bind in vitro to a phosphorylated tyrosine 759 peptide of glycoprotein 130 these data suggest SOCS-3 to be instrumental in the inhibition of the Janus kinase/STAT pathway by MAP kinases.
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PMID:The inhibition of interleukin-6-dependent STAT activation by mitogen-activated protein kinases depends on tyrosine 759 in the cytoplasmic tail of glycoprotein 130. 1076 98

Current research from both clinical and basic science perspectives indicates that cytokines play an important role in the genesis of cardiovascular pathology. Specifically, levels of cytokines such as interleukin-1 (IL-1), tumor necrosis factor- alpha (TNF- alpha), and interleukin-6 (IL-6) have been found to be elevated in both acute myocardial injury as well as situations of chronic dysfunction. Further, therapies directed primarily at interfering with cytokine action have suggested that such an immunomodulatory approach may be beneficial in some of these circumstances of myocardial injury. We recently reported that IL-1 beta induces a hypertrophic state in cultured neonatal rat cardiac myocytes that differs from other well described hypertrophic phenotypes in terms of myocardial gene expression (such as skeletal alpha -actin, sACT), an effect that appeared to co-localize with that of the negative regulator yin yang-1 (YY1).(1)In the present study, we further localize the area in the sACT promoter responsible for the IL-1 effect. These investigations indicate that sequences in and around the third upstream serum response element (SRE3) bind YY1 and are required for IL-1 beta mediated repression. This element is also capable of transferring both IL-1 beta and YY1-mediated transcriptional repression to a heterologous promoter. In support of an IL-1 beta induced post-translational modification of YY1 that results in an increase in DNA-binding activity,(32)P-labeling experiments reveal an increase in phosphorylated YY1 in IL-1 beta treated cells and phosphatase-treated myocyte nuclear proteins lose their ability to bind to the YY1 site. In summary, these results provide evidence that sequences within the SRE3 of the skeletal actin promoter represent an IL-1 beta response element and suggest that IL-1 beta activates the negative transcription factor YY1 by both transcriptional and post-transcriptional mechanisms.
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PMID:IL-1 beta increases abundance and activity of the negative transcriptional regulator yin yang-1 (YY1) in neonatal rat cardiac myocytes. 1086 Jul 74

Development of cytokine resistance is an important feature of melanoma cells during tumor progression. To study the mechanisms of interleukin-6 resistance, we examined an interleukin-6 sensitive (WM35) and an interleukin-6 unresponsive cell line (WM9). Interleukin-6 treatment resulted in rapid inhibition of cyclin-dependent kinase 2/cyclin E activity and accumulation of the hypophosphorylated retinoblastoma protein in WM35 but not in WM9 cells. In contrast to previous reports, no differences in the expression of the cyclin-dependent kinase 2 inhibitor p21Cip1/WAF1 upon interleukin-6 treatment were found in both cell lines. Interleukin-6-induced inhibition of cyclin-dependent kinase 2 was also not due to changes in protein expression of cyclin-dependent kinase 2, cyclin E, p27Kip1 and cdc25A, a phosphatase positively regulating cyclin-dependent kinase 2 activity. As it is established that interleukin-6 resistance of WM9 cells is not caused by differential interleukin-6 receptor expression, we studied whether this is due to defective interleukin-6 signaling in which activation of signal transducer and activator of transcription 3 is a critical step. WM9 cells showed reduced tyrosine phosphorylation, DNA binding, and delayed nuclear translocation of signal transducer and activator of transcription 3 as compared with WM35 cells. The kinase upstream of signal transducer and activator of transcription 3, Janus kinase 1, was constitutively tyrosine-phosphorylated in WM9 cells and did not respond to interleukin-6 with increased phosphorylation. As compared with WM35 cells, interleukin-6 treatment of WM9 cells was not paralleled by reduced activity of the mitogen-activated protein kinase kinase-1, which suppresses activation of signal transducer and activator of transcription 3. Our data suggest that resistance of advanced melanoma cells to interleukin-6 is associated with reduced inhibition of cyclin-dependent kinase 2, which appears to be a consequence of a complex alteration in interleukin-6 signal transduction.
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PMID:Interleukin-6-resistant melanoma cells exhibit reduced activation of STAT3 and lack of inhibition of cyclin E-associated kinase activity. 1144 60

We previously demonstrated that exposure of CCL39 lung fibroblasts to alpha-thrombin inhibits interleukin-6 (IL-6)-induced tyrosine phosphorylation of Stat3 (signal transducers and activators of transcription 3) via activation of mitogen-activated protein (MAP) kinase kinase 1 [Bhat et al. (1998) Arch. Biochem. Biophys. 350, 307-314]. In this study, using CCL39/MRC-5 cells, we investigated if additional signaling intermediates are involved in alpha-thrombin's inhibitory effects on IL-6-induced Stat3 signaling. We also determined if alpha-thrombin inhibits oncostatin M (OSM)-induced Stat3/Stat1, and interferon-gamma (IFN-gamma)-induced Stat1 tyrosine phosphorylation. We demonstrate that, although both IL-6 and OSM belong to the same cytokine family, alpha-thrombin inhibited only the IL-6-induced Stat3 tyrosine phosphorylation. The tyrosine phosphatase PTP1D coprecipitated with Stat3 from alpha-thrombin + IL-6, but not from alpha-thrombin + OSM-treated cells. Pretreatment of cells with a phosphatase inhibitor reversed the inhibitory actions of alpha-thrombin, suggesting a role for PTP1D in alpha-thrombin-mediated inhibition of IL-6-induced Stat3 signaling. Interestingly, alpha-thrombin failed to inhibit OSM- and IFN-gamma-induced Stat1 tyrosine phosphorylation. Cytokine-specific inhibition of the Stat3 signaling involving MAP kinase kinase 1 and PTP1D by alpha-thrombin may play an important role in regulation of gene expression.
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PMID:Involvement of tyrosine phosphatase PTP1D in the inhibition of interleukin-6-induced Stat3 signaling by alpha-thrombin. 1159 81

Expression of PTEN tumor suppressor gene has been known to dephosphorylate the phosphatidylinositol 3' kinase (PI3K) products on the 3 prime inositol ring, resulting in reduced Akt activation. Loss of PTEN expression in OPM2 and delta47 human myeloma lines led to high Akt activity toward insulin-like growth factor I (IGF-I). In contrast, mouse plasma cell tumor (PCT) lines, expressing wild type PTEN, did not respond to IGF-I for Akt activation. We demonstrated here that endogenous PTEN played a negative role in controlling Akt activity in both mouse PCT and NIH3T3 fibroblast lines by using anti-sense oligonucleotides against PTEN. To determine the role of src-homology 2-containing inositol 5' phosphatase (SHIP) in regulating the PI3K/Akt pathway, we manipulated its expression by down-regulation and overexpression in myeloma, PCT and NIH3T3 lines and analysed Akt activation. Our results showed that SHIP, unlike PTEN, did not affect Akt activity in all systems analysed, despite its ability to dephosphorylate a PI3K product. Although SHIP2 expression resulted in suppression of interleukin-6-mediated mitogen-activated protein kinase activation, expression of SHIP and SHIP2 in a PTEN-null myeloma line did not suppress Akt activity. Biologically, expression of only PTEN, but not SHIP and SHIP2, resulted in growth inhibition and increased apoptosis in OPM2 myeloma line. Together, our results have established the role of PTEN, but not SHIP and SHIP2, in negatively regulating the PI3K/Akt cascade and in myeloma leukemogenesis.
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PMID:PTEN, but not SHIP and SHIP2, suppresses the PI3K/Akt pathway and induces growth inhibition and apoptosis of myeloma cells. 1214 50

The hematopoietic-restricted protein Src homology 2-containing inositol-5-phosphatase (SHIP) blunts phosphatidylinositol-3-kinase-initiated signaling by dephosphorylating its major substrate, phosphatidylinositol-3,4,5-trisphosphate. As SHIP(-/-) mice contain increased numbers of osteoclast precursors, that is, macrophages, we examined bones from these animals and found that osteoclast number is increased two-fold. This increased number is due to the prolonged life span of these cells and to hypersensitivity of precursors to macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-kappa B ligand (RANKL). Similar to pagetic osteoclasts, SHIP(-/-) osteoclasts are enlarged, containing upwards of 100 nuclei, and exhibit enhanced resorptive activity. Moreover, as in Paget disease, serum levels of interleukin-6 are markedly increased in SHIP(-/-) mice. Consistent with accelerated resorptive activity, 3D trabecular volume fraction, trabecular thickness, number and connectivity density of SHIP(-/-) long bones are reduced, resulting in a 22% loss of bone-mineral density and a 49% decrease in fracture energy. Thus, SHIP negatively regulates osteoclast formation and function and the absence of this enzyme results in severe osteoporosis.
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PMID:SHIP-deficient mice are severely osteoporotic due to increased numbers of hyper-resorptive osteoclasts. 1216 49

The development of in vitro cell culture methods has made it possible to study bone cell metabolism and growth and obtain a deeper insight into the pathophysiology of common orthopedic diseases such as osteoporosis. After analyzing the effect of two essential amino acids, L-arginine (Arg) and L-lysine (Lys), in previous in vitro and in vivo studies, the present authors investigated the administration of Arg and Lys in osteoblasts derived from human osteopenic bone. After isolation, osteoblasts were cultured in DMEM supplemented with either Arg (0.625 mg/ml/day, Arg Group) or Lys (0.587 mg/ml/day, Lys Group), or both of them (Arg-Lys Group), whereas the Control Group was sham-treated. After 7 days the following parameters were tested in all groups: MTT proliferation test, Alkaline Phosphatase (ALP), Nitric Oxide (NO), Calcium (Ca), Phosphorus (P), Osteocalcin (OC), C-Terminal Procollagen type I (PICP), Interleukin-6 (IL-6), Transforming Growth Factor-beta 1 (TGF-beta 1), Platelet Derived Growth Factor (PDGF) and Insulin-Like Growth Factor-I (IGF-I). Results were compared with those obtained from human healthy bone to verify the effect of the amino acids on osteoblasts derived from pathological tissue. In addition, a comparison was also made with the results obtained from rat osteopenic bone to assess reliability of the in vitro model. The current results support previous findings and indicate that Arg and Lys stimulation has a positive effect on osteoblast proliferation, activation and differentiation. Therefore, administration of these amino acids may be useful in clinical treatment and prevention of osteoporosis.
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PMID:Human osteopenic bone-derived osteoblasts: essential amino acids treatment effects. 1260 15

Multiple myeloma (MM) is a proliferative disorder of monoclonal plasma cells which accumulate in human bone marrow, and myeloma cells proliferate in response to a cytokine, interleukin-6 (IL-6). We recently found that MPC-1- CD49e- immature myeloma cells expressing CD45 form a proliferating population in MM. IL-6 activates at least two intracellular pathways including signal transducer and activator of transcription 3 (STAT3) and extracellular signal-regulated kinase 1/2 (ERK1/2) following the activation of Janus kinases (JAKs) via its receptor complexes composed of the IL-6 receptor alpha chain and gp130. Although the roles of CD45 have been extensively studied for antigen receptors in B and T cells, its physiological consequences in other hematopoietic cells remain largely unknown. Myeloma cells expressing CD45 antigens which contain the activation of src family protein-tyrosine kinases (PTKs) independent of IL-6 stimulation proliferate in response to IL-6, whereas the proliferation of CD45- cells which lack a considerable activity of the src family PTKs is not promoted by IL-6. The STAT3 and ERK1/2 pathways are similarly activated by IL-6 in both cells either expressing or not expressing CD45. In this review, we argue a novel mechanism of proliferation of myeloma cells, in that the activation of both STAT3 and ERK1/2 is not sufficient for IL-6-induced proliferation which further requires IL-6-independent activation of the src family kinases associated with CD45 phosphatase. We propose that the cellular context, such as CD45 expression and src family kinase activation, is crucial for myeloma cells to proliferate in response to IL-6.
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PMID:Interleukin-6, CD45 and the src-kinases in myeloma cell proliferation. 1456 47

We have previously shown that non-pathogenic Gram-negative Bacteroides vulgatus induces transient RelA phosphorylation (Ser-536), NF-kappaB activity, and pro-inflammatory gene expression in native and intestinal epithelial cell (IEC) lines. We now demonstrate that 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) but not prostaglandin E(2) inhibits lipopolysaccharide (LPS) (B. vulgatus)/LPS (Escherichia coli)-induced RelA phosphorylation and interleukin-6 gene expression in the colonic epithelial cell line CMT-93. This inhibitory effect of 15d-PGJ(2) was mediated independently of LPS-induced IkappaBalpha phosphorylation/degradation and RelA nuclear translocation as well as RelA DNA binding activity. Interestingly, although B. vulgatus induced nuclear expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in native epithelium of monoassociated Fisher rats, PPARgamma-specific knock-down in CMT-93 cells using small interference RNA failed to reverse the inhibitory effects of PPARgamma agonist 15d-PGJ(2), suggesting PPARgamma-independent mechanisms. In addition, 15d-PGJ(2) but not the synthetic high affinity PPARgamma ligand rosiglitazone triggered ERK1/2 phosphorylation in IEC, and most importantly, MEK1 inhibitor PD98059 reversed the inhibitory effect of 15dPGJ(2) on LPS-induced RelA phosphorylation and interleukin-6 gene expression. Calyculin A, a specific phosphoserine/phospho-threonine phosphatase inhibitor increased the basal phosphorylation of RelA and reversed the inhibitory effect of 15d-PGJ(2) on LPS-induced RelA phosphorylation. We further demonstrated in co-immunoprecipitation experiments that 15d-PGJ(2) triggered protein phosphatase 2A activity, which directly dephosphorylated RelA in LPS-stimulated CMT-93 cells. We concluded that 15d-PGJ(2) may help to control NF-kappaB signaling and normal intestinal homeostasis to the enteric microflora by modulating RelA phosphorylation in IEC through altered protein phosphatase 2A activity.
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PMID:15-deoxy-delta12,14-prostaglandin J2-mediated ERK signaling inhibits gram-negative bacteria-induced RelA phosphorylation and interleukin-6 gene expression in intestinal epithelial cells through modulation of protein phosphatase 2A activity. 1519 53

Interleukin-6 (IL-6) increases metalloproteinase-13 (MMP-13) gene expression by increasing phosphorylated c-Jun and by inhibiting serine/threonine phosphatase-2A (PP2A) activity. We investigated the mechanisms by which IL-6 induces c-Jun phosphorylation and PP2A inactivation in Rat-1 fibroblasts. We show that IL-6 increased MMP-13 mRNA, phosphorylated c-Jun, and activator protein 1 (AP1) binding activity without increasing c-Jun-N-terminal kinase (JNK) activity. These effects did not seem to be mediated by ERK, p38 MAP kinase, phosphatidylinositol-3-kinase, calmoduline-dependent protein kinase, protein kinase C (PKC) or protein kinase A since inhibition with specific inhibitors did not abrogate these effects. IL-6 increases PP2A catalytic subunit tyrosine phosphorylation. Inhibition of the tyrosine kinase Jak2, with the specific inhibitor AG490, abrogated this effect. Likewise, this Jak2 inhibitor blocked the effects of IL-6 on c-Jun phosphorylation, AP1 binding activity and metalloproteinase-13 gene expression. We conclude that IL-6 increases MMP-13 gene expression by activation of Jak2, resulting in tyrosine phosphorylation of the catalytic subunit of PP2A, which in turn decreases PP2A activity and prolongs c-Jun phosphorylation.
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PMID:Interleukin-6 increases rat metalloproteinase-13 gene expression through Janus kinase-2-mediated inhibition of serine/threonine phosphatase-2A. 1560 21


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