Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We recently reported that insulin stimulation results in the serine phosphorylation of STAT3 (signal transducer and activator of transcription-3). In the present study, we identified serine 727 as the site of insulin-stimulated STAT3 serine phosphorylation. This phosphorylation event occurs independent of tyrosine phosphorylation. Furthermore, interleukin-6-induced tyrosine phosphorylation can occur independent of serine phosphorylation, demonstrating that these two phosphorylation pathways are mechanistically unrelated. Selective activation of the JNK and p38 family of mitogen-activated protein (MAP) kinases by anisomycin treatment did not result in the phosphorylation of STAT3. In contrast, activation of the ERK MAP kinase pathway with both insulin and osmotic shock resulted in the serine phosphorylation of STAT3. In addition, expression of a dominant-interfering Ras mutant (N17Ras) or treatment with the specific MEK inhibitor (PD98059) prevented the insulin stimulation of STAT3 serine phosphorylation. Blockade of ERK activation by expression of the MAP kinase phosphatase (MKP-1) had no effect on insulin-stimulated STAT3 serine phosphorylation. Together, these data demonstrate that the insulin-stimulated serine phosphorylation of STAT3 occurs by a MEK-dependent pathway that is independent of ERK activation.
 ...
PMID:Signal transducer and activator of transcription-3 serine phosphorylation by insulin is mediated by a Ras/Raf/MEK-dependent pathway. 932 21

We previously showed that sphingosine 1-phosphate (SPP) acts as a second messenger for tumor necrosis factor alpha-induced interleukin-6 (IL-6) synthesis in osteoblast-like MC3T3-E1 cells. In the present study, we further investigated the mechanism of IL-6 synthesis induced by SPP in MC3T3-E1 cells. SPP significantly induced p42/p44 mitogen-activated protein (MAP) kinase activity. PD98059, an inhibitor of MAP kinase kinase, suppressed SPP-induced IL-6 synthesis as well as SPP-induced MAP kinase activation. The patterns of both inhibitions were similar. TMB-8, an inhibitor of Ca2+ mobilization from intracellular Ca2+ stores, significantly suppressed the SPP-induced IL-6 synthesis. These results strongly suggest that SPP-induced IL-6 synthesis is mediated via p42/p44 MAP kinase activation in osteoblast-like cells and that the SPP-induced IL-6 synthesis is dependent on intracellular Ca2+ mobilization.
 ...
PMID:Activation of mitogen-activated protein kinase is involved in sphingosine 1-phosphate-stimulated interleukin-6 synthesis in osteoblasts. 941 15

Prostaglandin F2alpha (PGF2alpha) significantly induced p42/p44 mitogen-activated protein (MAP) kinase activity in osteoblast-like MC3T3-E1 cells. PD98059, a selective inhibitor of MAP kinase kinase, inhibited PGF2alpha-induced interleukin-6 (IL-6) synthesis as well as PGF2alpha-induced p42/p44 MAP kinase activation. PD98059 suppressed the IL-6 synthesis induced by 12-O-tetradecanoylphorbol-13-acetate (TPA), a protein kinase C (PKC) activator, or NaF, an activator of heterotrimeric GTP-binding protein, as well as the p42/p44 MAP kinase activation by TPA or NaF. Calphostin C, a highly potent and specific inhibitor of PKC, inhibited the PGF2alpha-induced p42/p44 MAP kinase activity. These results strongly suggest that PKC-dependent p42/p44 MAP kinase activatioin is involved in PGF2alpha-induced IL-6 synthesis in osteoblasts.
 ...
PMID:p42/p44 mitogen-activated protein kinase activation is involved in prostaglandin F2alpha-induced interleukin-6 synthesis in osteoblasts. 1037 4

Ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF) are members of a subfamily of related cytokines that share gp130 as common signal-transducing receptor component. CNTF has recently been demonstrated to induce increased survival and neuronal differentiation of P19 embryonal carcinoma (EC) cells; however, the molecular mechanisms underlying these effects are still elusive. Here we report that CNTF and LIF, but not interleukin-6, activated signal transducers and activators of transcription (STAT)-reporter constructs in P19 EC cells. Supershift analysis revealed that the STAT-element binding complex contained the transcription factor Stat3. Binding of Stat3 was inhibited by protein tyrosine kinase inhibitors, but not by the broad serine/threonine protein kinase inhibitor, H7. However, H7 inhibited CNTF-induced Stat3 transactivation. Using a dominant-negative p21ras construct and a specific inhibitor of mitogen-activated protein kinase kinase (MEK; PD098059) we demonstrated that CNTF-induced Stat3 transactivation was independent of the p21ras-mitogen-activated protein kinase (MAPK) pathway, while CNTF-induced MAPK activation was p21ras- and MEK-dependent. Taken together, our results demonstrate the activation of the p21ras-MAPK and STAT signal transduction pathways in response to CNTF and LIF in P19 EC cells and reveal that there is no modulating crosstalk between these pathways. Furthermore, our data suggest that CNTF- and LIF-induced Stat3 activation in P19 EC cells involves an H7-sensitive p21ras/MAPK- and Ca(2+)-independent kinase.
 ...
PMID:Cytokine signal transduction in P19 embryonal carcinoma cells: regulation of Stat3-mediated transactivation occurs independently of p21ras-Erk signaling. 1047 31

Astrogliosis is a hallmark of prion diseases. Finding ways of inhibiting astrocyte proliferation may be beneficial to treating these diseases. PrP106-126 a peptide fragment of the prion protein induces proliferation of astrocytes. The mechanism of its action was studied in detail. Induction of astrocyte proliferation in culture requires cytokines interleukin-1 and interleukin-6 released from microglia in the presence of PrP106-126. However, the increased release of these cytokines is insufficient without direct effects of PrP106-126 on astrocytes. PrP106-126 induces increased progression through the cell cycle to late G1 and enhances the level of both p53 and phosphorylated ERKs in astrocytes. PrP106-126-induced proliferation of astrocytes in culture can be inhibited by antibodies to cytokines or by MEK inhibitors.
 ...
PMID:A model for the mechanism of astrogliosis in prion disease. 1099 49

Interleukin-6 (IL-6) is a pleitrophic cytokine that not only regulates growth and differentiation of many cell types, but also induces production of acute phase proteins (AAP) in hepatocytes. Our previous works have demonstrated that both PI 3-K/Akt and STAT3 pathways were concomitantly activated and cooperatively mediated the anti-apoptotic effect of IL-6. This investigation reports that IL-6 protected cells against apoptosis induced by a variety of agents including, TGF-beta, UV and retinoic acid (RA) in Hep3B cells, suggesting that IL-6 is a fundamental determinant of hepatic cell survival. Mcl-1, but not other Bcl-2 family members, was rapidly up-regulated by IL-6, with a peak (approximately 3-4-fold) appearing at 4 h. Transient transfection of cells with a mcl-1 antisense vector, resulting in a 50-60% reduction of the anti-apoptotic effect of IL-6, indicating that Mcl-1 is a downstream effector of IL-6. Which signaling pathway transduced by IL-6 responsible for the Mcl-1 up-regulation was further investigated. In Hep3B cells, the JAK/STAT3, ERK, and PI 3-K/Akt pathways were activated by IL-6 stimulation. Blocking JAK/STAT3 activation with a dominant-negative mutant STAT3F or a JAK inhibitor AG490 could not influence IL-6-mediated Mcl-1 up-regulation. Similarly, PD98059 treatment, a MEK specific inhibitor, also failed to inhibit Mcl-1 expression. However, the IL-6-induced Mcl-1 up-regulation was effectively attenuated in the presence of PI 3-K inhibitors, LY294002 and wortmannin. Expression of dominant-negative Akt, but not Etk, could abrogate the IL-6-induced increase of Mcl-1. In conclusion, our results suggest that the anti-apoptotic effect of IL-6 is mediated, at least in part, by Mcl-1 expression and that is mainly through the PI 3-K/ Akt-dependent pathway.
 ...
PMID:The involvement of PI 3-K/Akt-dependent up-regulation of Mcl-1 in the prevention of apoptosis of Hep3B cells by interleukin-6. 1131 1

Activation of signal transducer and activator of transcription 3 (STAT3) by interleukin-6 (IL-6) involves phosphorylation of Tyr-705 and Ser-727, both of which are critical for STAT3 transactivation. Here, we demonstrate that IL-6 activates Rac-1 and SEK-1/MKK-4 of the stress-activated protein kinase pathway, as well as protein kinase Cdelta (PKCdelta), as indicated by PKCdelta Thr-505 phosphorylation. However, JNK-1, the end point kinase of the stress-activated protein kinase pathway signal transduction cascade, is not activated by IL-6. PKCdelta was found to be associated with SEK-1/MKK-4 in unstimulated HepG2 cells but rapidly dissociates from SEK-1/MKK-4 upon IL-6 stimulation to become associated with STAT3. Inhibition of PKCdelta using rottlerin (6 microm) or by overexpression of dominant negative PKCdelta demonstrates that PKCdelta kinase activity is required for STAT3 Ser-727 phosphorylation and transactivation but not for STAT3 Tyr-705 phosphorylation or nuclear import. PKCdelta signals downstream of Rac-1 and SEK-1/MKK-4, because enhanced STAT3 transactivation induced by overexpression of constitutive active RacV12 was strongly abrogated by rottlerin, whereas IL-6-induced SEK-1/MKK-4 Thr-223 phosphorylation was not affected under these conditions. Studying the kinetics of STAT3 and PKCdelta phosphorylation in cytoplasmic and nuclear fractions revealed that STAT3 Tyr-705 phosphorylation and nuclear translocation precedes PKCdelta Thr-505 and STAT3 Ser-727 phosphorylation. Furthermore, the IL-6-induced PKCdelta Thr-505 and STAT3 Ser-727 phosphorylation were only observed in nuclear fractions of HepG2 cells. These results demonstrate that IL-6-induced STAT3 transactivation involves the sequential activation of Rac-1 and SEK-1/MKK-4, which leads to nuclear translocation of PKCdelta by release from a SEK-1/MKK-4-containing complex. Our results further indicate that PKCdelta-mediated STAT3 Ser-727 phosphorylation is mainly a nuclear event.
 ...
PMID:Sequential activation of Rac-1, SEK-1/MKK-4, and protein kinase Cdelta is required for interleukin-6-induced STAT3 Ser-727 phosphorylation and transactivation. 1133 11

Interleukin-6 is a pleiotropic cytokine that mediates cellular communication both in physiological and pathological states. In this work, we demonstrate that 50 ng/mL IL-6 increases the survival of retinal ganglion cells (RGCs) after 48 h in culture. This effect was blocked by an intracellular Ca(+2) chelator, by inhibition of ryanodinic receptors and by an inhibitor of L-type Ca(+2) channels. IL-6 effect is mediated by PKC, tyrosine kinase, PI3-kinase and MEK activity. The blockade of polypeptide release also abolished the effect of IL-6. These results suggest a role for this cytokine during the development of the central nervous system (CNS).
 ...
PMID:Interleukin-6 increases the survival of retinal ganglion cells in vitro. 1143 Oct 3

The present study examined the role of calcineurin in insulin-like growth factor (IGF)-1-induced hypertrophy in primary cultures of adult rat ventricular myocytes (ARVM), prepared from the ventricles of 14-16-week-old male Sprague-Dawley rats. The effects of several humoral factors, including phenylephrine, angiotensin II, endothelin-1, IGF-1 and interleukin-6, on the morphology of ARVM were studied. Myocyte surface area was significantly increased by IGF-1 (2,268 +/- 571 to 3,018 +/- 836 microm2, p < 0.01), but not by other humoral factors. This hypertrophic effect of IGF-1 was blocked by genistein (tyrosine kinase inhibitor), PD98059 (MEK inhibitor). These findings suggest that IGF-1 produces ARVM hypertrophy by a tyrosine kinase-MEK mediated pathway as has been reported in neonatal cardiomyocytes. IGF-1-mediated ARVM hypertrophy was also attenuated by cyclosporine A (calcineurin inhibitor), and staurosporine and chelerythrine (protein kinase C inhibitors). IGF-1 markedly increased calcineurin activity (8.7 +/- 1.2 to 98.0 +/- 54.3 pmol x h(-1) mg(-1), p < 0.01), and this activation was completely blocked by pre-treatment with cyclosporine A (8.5 +/- 11.4pmol x h(-1) x mg(-1), p < 0.01) and chelerythrine (2.3 +/- 2.7 pmol x h(-1) mg(-1), p < 0.01). It appears that IGF-1 activates calcineurin by a protein kinase C-dependent pathway. Increased mRNA expression of atrial natriuretic factor by IGF-1 was inhibited by cyclosporine A (p < 0.01). The findings indicate that IGF-1 induces ARVM hypertrophy by protein kinase C and calcineurin-related mechanisms. The fact that elevated calcineurin activity and induced atrial natriuretic factor mRNA expression by IGF-1 were blocked by cyclosporine A further supports the hypothesis that calcineurin is critically involved in IGF-1-induced ARVM hypertrophy.
 ...
PMID:Role of calcineurin in insulin-like growth factor-1-induced hypertrophy of cultured adult rat ventricular myocytes. 1154 82

Interleukin-6 (IL-6), a multifunctional cytokine, has recently been implicated in human cervical cancer, though the mechanism remains elusive. This study demonstrates that the anti-apoptotic protein Mcl-1 and IL-6 was concomitantly expressed in human cervical cancer tissues and cell lines, but not in normal cervix tissues. Upon IL-6 treatment, Mcl-1, but not other Bcl-2 family members, was rapidly up-regulated peaking at 4-8 h in human cervical cancer C33A cells. Supporting this observation, using anti-IL-6 or anti-IL-6 receptor antibody to interrupt the IL-6 autocrine loop in SiHa cells significantly reduced cellular level of Mcl-1. This study hypothesizes that the expression of Mcl-1 in cervical cancer cells is regulated by IL-6. The matter of which signaling pathways transduced by IL-6 is responsible for the Mcl-1 up-regulation is further investigated herein. Blocking the STAT3 or MAPK pathway with dominant-negative mutant STAT3F or the MEK inhibitor PD98059 failed to inhibit IL-6-mediated Mcl-1 expression. Meanwhile, the IL-6-induced Mcl-1 up-regulation was effectively abolished by treatment with PI 3-K inhibitors, LY294002. Additionally, overexpression of dominant-negative (dn) Akt in C33A cells could inhibit the IL-6-induced increase of Mcl-1. Finally, overexpression of IL-6 in C33A cells caused a markable resistance to apoptosis induced by doxorubicin or cisplatin. Transient transfection of IL-6-overexpressed cells with a mcl-1 antisense vector, leading to the attenuation of their apoptosis-resistant activity. In conclusion, the data herein suggest that IL-6 regulated the mcl-1 expression via a PI 3-K/Akt-dependent pathway that may facilitate the oncogenesis of human cervical cancer by modulating the apoptosis threshold.
 ...
PMID:The anti-apoptotic role of interleukin-6 in human cervical cancer is mediated by up-regulation of Mcl-1 through a PI 3-K/Akt pathway. 1159 85


1 2 3 4 5 6 7 8 Next >>