HUMANGGP:021712 - FACTA Search

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Query: HUMANGGP:021712 (IL-6)
58,419 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have investigated the activation of mitogen-activated protein kinase (MAP-kinase) in KB human epidermoid carcinoma cells treated with interleukin 1 (IL-1). MAP-kinase activity was transient; the time required for activity to reach a maximal level was dependent upon the dose of IL-1, ranging from 15 minutes to 45 minutes. The level of kinase induction correlated well with dose-response curves for two characteristic IL-1-induced responses, PGE2 and IL-6 production. MAP-kinase activity returned to basal levels within 2 hours regardless of the amount of IL-1 added to the system. Exposure of KB cells to free IL-1 was accordingly restricted to periods of 2 hours or less, by replacing IL-1 with an excess of IL-1 receptor antagonist. Even after 2 hours exposure, the ability of IL-1 to induce IL-6 or PGE2 was still IL-1ra-inhibitable by more than 80%, suggesting that events downstream of, or parallel to MAP-kinase activation, requiring the continual formation of new IL-1 receptor complexes, are needed to fully elicit these responses. Two general serine/threonine kinase inhibitors, K252a and quercetin, were found to strongly inhibit MAP kinase in vivo with ED50s of c. 100 nM and 30 microM, respectively. At these concentrations, both compounds effectively inhibited IL-1-driven PGE2 and IL-6 induction without affecting general protein synthesis or secretion. Other non-selective kinase inhibitors had less effect on MAP-kinase activation or IL-1-induced biological responses. The transient activation of MAP-kinase induction correlated strikingly with activation of the transcription factor NF-kappa B. IL-1-induced NF-kappa B activation was, however, relatively insensitive to inhibition by K252a or quercetin. We suggest that MAP-kinase is likely to be a necessary, but not sufficient, intermediate in some (IL-6, PGE2 induction) but not all (NF-kappa B activation) IL-1 responses in these cells.
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PMID:Evidence that MAP (mitogen-activated protein) kinase activation may be a necessary but not sufficient signal for a restricted subset of responses in IL-1-treated epidermoid cells. 133 84

IL-11 is a multifunctional cytokine biologically related to IL-6, leukemia inhibitory factor (LIF), oncostatin M (OSM) and ciliary neurotrophic factor (CNTF). It has been shown that these cytokines can utilize common signal transducer, gp130. We have demonstrated that Jak tyrosine kinases, MAP kinases and pp90rsk are highly activated by IL-11 and related cytokines. In addition, we have identified pp90rsk as one of the H7 sensitive protein kinases critical for primary response gene expression induced by IL-11. Furthermore, activation of 3CH134 (a MAP kinase phosphatase) gene by IL-11 suggested that a MAP kinase phosphatase may be involved in IL-11-mediated signal transduction. Our data also suggested that tyrosine phosphorylation of Stat91 and related transcriptional factors is involved in IL-11 signaling but is not sufficient for the activation of primary response genes such as JunB, tis11, tis8 and MAP kinase phosphatase in mouse preadipocytes. The understanding of signal transduction pathways mediated by IL-11 and related cytokines may help to define the common and unique biological properties of these growth factors.
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PMID:Interleukin (IL)-11--mediated signal transduction. 754 69

Vascular endothelial cell (EC) injury or activation by LPS plays a critical role in the pathogenesis of Gram-negative meningitis and endotoxic shock. EC do not express membrane CD14, but respond to LPS in a soluble CD14-dependent manner. The signal transduction mechanisms involved in LPS-induced EC responses are largely unknown. We used bovine and human brain microvessel EC (BBMEC, and HBMEC) to study LPS-induced protein tyrosine phosphorylation. LPS rapidly induced the tyrosine phosphorylation of several proteins in BBMEC and HBMEC, which was detectable by 5 to 15 min, reached a maximum by 30 min, and declined by 60 to 90 min. The increase in tyrosine phosphorylation was apparent following stimulation with LPS at 0.1 ng/ml and was dose dependent up to 100 ng/ml. Similar changes in tyrosine phosphorylation were induced by smooth and rough LPS as well as lipid A, but not by the inactive lipid A analogue, Rhodopseudomonas sphaeroides diphosphoryl lipid A. Pretreatment of EC with the tyrosine kinase inhibitor, herbimycin A, inhibited LPS-stimulated protein tyrosine phosphorylation and LPS-mediated lactic dehydrogenase release from BBMEC and IL-6 release from HBMEC in a dose-dependent manner. Three proteins with apparent m.w. of 44, 42, and 41 kDa were predominant among the LPS-induced tyrosine phosphoproteins, and they were identified as mitogen-activated protein kinase isoforms ERK1, ERK2, and p38, respectively. LPS-induced protein tyrosine phosphorylation in HBMEC and BBMEC was soluble CD14 dependent, since pretreatment of these cells with anti-hCD14 mAb inhibited the LPS-induced tyrosine phosphorylation of p44, p42, and p41. Additionally, LPS induced a mobility shift in p44 and p42 mitogen-activated protein kinase isozymes, which was inhibited by herbimycin A pretreatment of the EC. These findings demonstrate for the first time that increased protein tyrosine phosphorylation and activation of mitogen-activated protein kinases occur rapidly after LPS stimulation of EC in the presence of soluble CD14. Our data also suggest that a herbimycin-sensitive step, presumably a tyrosine kinase, is involved in mediating LPS-induced human EC activation and IL-6 secretion.
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PMID:Lipopolysaccharide stimulates the tyrosine phosphorylation of mitogen-activated protein kinases p44, p42, and p41 in vascular endothelial cells in a soluble CD14-dependent manner. Role of protein tyrosine phosphorylation in lipopolysaccharide-induced stimulation of endothelial cells. 756 Nov 8

Oncostatin-M (OSM) is a potent mitogen for Kaposi's sarcoma (KS) cells. We studied signaling by the OSM receptor in three AIDS-related KS lines and show induction of tyrosine phosphorylation of 145-, 120-, 85-, and 42-kD substrates. The 42-kD substrate was identified as p42MAPK (mitogen-activated protein kinase), also known as ERK-2. This serine/threonine kinase relays mitogenic signals from receptor tyrosine protein kinases (TPKs) or receptor-associated TPKs to transcriptional activators. The OSM dose dependence for MAP kinase activation and induction of KS cell growth were almost identical, suggesting functional linkage. MAP kinase activation was dependent on tyrosine phosphorylation, and both OSM-induced MAP kinase activity and KS cell growth could be suppressed by TPK inhibitors, genistein and geldanomycin. OSM also stimulated tyrosine phosphorylation of similar substrates and MAP kinase activity in human vein endothelial cells. While it has been proposed that the OSM receptor may include the gp130 subunit of the IL-6 receptor and alpha-chain of leukemia inhibitory factor (LIF) receptor, neither LIF nor r.IL-6 induced tyrosine protein phosphorylation or p42MAPK activation in KS cells. However, r.IL-6 did stimulate tyrosine phosphorylation and p42MAPK activity in the human B cell line, AF-10, while OSM and LIF exerted no effects. Our results indicate that, although the OSM and IL-6 receptors share a common signaling pathway, this pathway is selectively activated by OSM in Kaposi's cells.
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PMID:Oncostatin-M stimulates tyrosine protein phosphorylation in parallel with the activation of p42MAPK/ERK-2 in Kaposi's cells. Evidence that this pathway is important in Kaposi cell growth. 768 64

Interleukin-6 is a multifunctional cytokine which regulates various aspects of the host immune response. Here we show that signaling events transferred by IL-6 in monocytes and the U937 human monocytic leukemia cell line lead to the phosphorylation of the small heat shock protein (Hsp)27. Phosphorylation of Hsp27 is both dose- and time-dependent. In the absence of NaF, a serine/threonine phosphatase inhibitor, IL-6 failed to initiate Hsp27 phosphorylation in vitro. IL-6 also failed to phosphorylate Hsp27 when cells had been deactivated with tyrosine kinase inhibitors such as genistein. The capacity of cellular extracts to phosphorylate Hsp27 could be, however, restored when either immunoprecipitated activated MAP kinase or purified MAPKAP kinase 2 was added to cell lysates. These findings suggest that IL-6-mediated phosphorylation of Hsp27 results from activation of MAPKAP kinase 2, a serine/threonine kinase which is activated by MAP kinase. Taking together, our findings indicate that IL-6-induced activation of MAP kinase by IL-6 entails the activation of MAPKAP kinase 2 and subsequent phosphorylation of the Hsp27.
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PMID:Interleukin (IL)-6 signaling leads to phosphorylation of the small heat shock protein (Hsp)27 through activation of the MAP kinase and MAPKAP kinase 2 pathway in monocytes and monocytic leukemia cells. 786 66

Substance P (SP) is a tachykinin involved in the regulation of inflammatory processes. Tachykinins bind to three subtypes of neurokinin (NK) receptors. However, recently we demonstrated that monocytes express a SP binding site that is not one of the known NK receptors. Activation of this SP receptor leads to the stimulation of MAP kinase in monocytes. In the present paper we show that this novel SP binding site is coupled to a GTP binding protein of the Gi alpha 1/2 subclass. Triggering of the SP receptor leads to a rapid rise in cytosolic calcium. In a more sustained way, SP stimulates phospholipase D (PLD) activity in human monocytes. The effects of SP on calcium, PLD, and MAP kinase activity can be blocked by pretreatment of the cells with pertussis toxin, which is in agreement with receptor coupling to Gi. At a functional level, stimulation of the non-NK SP receptor on monocytes results in the induction of IL-6 production. We show here that the order of potency for activation of monocytes by various ligands is directly related to the Ki for displacement of labeled SP by these ligands. Therefore, our data strongly suggest that the effects of SP are mediated via the novel SP receptor we recently described.
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PMID:Activation of human monocytes via a non-neurokinin substance P receptor that is coupled to Gi protein, calcium, phospholipase D, MAP kinase, and IL-6 production. 793 May 88

We have previously shown that the IL-6R in a growth-responsive B cell line, AF10, induces activation of mitogen-activated protein (MAP) kinase. Here we demonstrate the activation of Raf-1 and MEK-1, which act as a MAP kinase kinase kinase and a MAP kinase kinase, respectively, in the MAP kinase cascade induced by IL-6 in AF10 cells. IL-6 also induced tyrosine phosphorylation of the signaling transducing subunit of the IL-6R in AF10 cells, along with tyrosine phosphorylation of the gp130-associated tyrosine protein kinase JAK1 and the adaptor molecule p52shc. Although induction of tyrosine phosphorylation and activation of MAP kinase by IL-6 in a differentiation-responsive B cell line, SKW 6.4, were below the limits of detection, the phorbol ester PMA did activate Raf-1, MEK-1, and MAP kinase without inducing the phosphorylation of gp130, JAKs, or p52shc. These results suggest that JAK kinase family members associated with the IL-6R may participate in the activation of MAP kinase in AF10 cells by way of an adaptor protein and Ras-dependent kinase cascade.
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PMID:Involvement of Janus kinases, p52shc, Raf-1, and MEK-1 in the IL-6-induced mitogen-activated protein kinase cascade of a growth-responsive B cell line. 796 20

IL-6 is a multi-functional cytokine that utilizes 80-kDa ligand-binding and 130-kDa signal-transducing subunits to stimulate diverse cellular responses. Although IL-6R ligation has been associated with tyrosine protein phosphorylation and activation of an unidentified serine/threonine kinase, very little is known about the intermediary signaling events between the cell membrane and the nucleus. rIL-6 treatment of the human B cell line, AF-10, induced MAP kinase (mitogen-activated protein kinase) activity as determined by in vitro phosphorylation of microtubule-associated protein-2 (MAP-2) and the synthetic peptide APRTPGGRR, corresponding to amino acids 95-98 of bovine myelin basic protein. The kinetics of the response was rapid and dependent on the dose of rIL-6. The response was cytokine specific, did not require the presence of extracellular Ca2+, and was minimally affected by the presence of staurosporine. MAP kinase activation in AF-10 cells occurred in parallel with appearance of 42- and 44-kDa tyrosine phosphoproteins (p42 and p44). Moreover, MAP kinase activation was diminished when AF-10 cells were stimulated with rIL-6 in the presence of tyrosine protein kinase inhibitors, genistein and geldanomycin. p42 and p44 co-electrophoresed on SDS-PAGE with extracellular signal-related kinase (ERK)-2, and ERK-1, respectively; both are members of the ERK family. In addition to p42MAPK and p44MAPK, rIL-6 also activated a MAP-2 kinase that eluted at a lower salt concentration (20 to 60 mM NaCl, peak I) from Mono-Q resin than p42MAPK (120 to 180 mM NaCl, peak II). The identify of this kinase is unknown but it is not an MPB kinase or a protein that exhibits immunoreactivity with anti-ERK antisera. In another IL-6-responsive B cell line, SKW6.4, rIL-6-activated peak I MAP-2 kinase but failed to activate ERK-2. The protein kinase C agonist, PMA, did, however, activate ERK-2 in SKW6.4 cells. These results show that the pleiotrophic cytokine, IL-6, activates p42MAPK/ERK-2 and at least one other serine/threonine kinase in B cell lines.
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PMID:Recombinant IL-6 activates p42 and p44 mitogen-activated protein kinases in the IL-6 responsive B cell line, AF-10. 838 18

Most cytokines stimulate the p21ras pathway, leading to MAP kinase activation. One exception is interleukin-4 (IL-4), which has been shown not to activate this pathway in hematopoietic cells. However, IL-4 acts on a broad range of cells, including keratinocytes, in which it induces IL-6 production. We report here that IL-4 stimulation of human keratinocytic cell lines or primary cultures activates MAP kinase. In these cells, IL-4 stimulation induces the tyrosine phosphorylation of p42/44 MAP kinase as well as its catalytic activity. We also observed an increased phosphorylation of p46shc, an SH2-containing protein involved in the Ras pathway, as a result of IL-4 stimulation in human keratinocytic cell lines but not in T lymphocytes.
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PMID:Interleukin-4 induces activation of mitogen-activated protein kinase and phosphorylation of shc in human keratinocytes. 862 75

Ceramide, produced through either the induction of SM hydrolysis or synthesized de novo transduces signals mediating differentiation, growth, growth arrest, apoptosis, cytokine biosynthesis and secretion, and a variety of other cellular functions. A generalized ceramide signal transduction scheme is shown in Fig. 2 in which ceramide is generated through the activation of distinct SMases residing in separate subcellular compartments in response to specific stimuli. Clearly, specificity of cellular responses to ceramide depends upon many factors which include the nature of the stimulus, co-stimulatory signals and the cell type involved. Ceramide derived from neutral SMase activation is thought to be involved in modulating CAPK and MAP kinases, PLA2 (arachidonic acid mobilization), and CAPP while ceramide generated through acid SMase activation appears to be primarily involved in NF-kappa B activation. While there is no apparent cross-talk between these two ceramide-mediated signalling pathways, there is likely to be significant cross-talk between ceramide signalling and other signal transduction pathways (e.g., the PKC and MAP kinase pathways). Other downstream targets for ceramide action include Cox, IL-6 and IL-2 gene expression, PKC zeta, Vav, Rb, c-Myc, c-Fos, c-Jun and other transcriptional regulators. Many, if not all, of these ceramide-mediated signalling events have been identified in the various cells comprising the immune system and are integral to the optimal functioning of the immune system. Although the role of the SM pathway and the generation of ceramide in T and B lymphocytes have only recently been recognized, it is clear from these studies that signal transduction through SM and ceramide can strongly affect the immune response, either directly through cell signalling events, or indirectly through cytokines produced by other cells as the result of signalling through the SM pathway. An overview of the signalling mechanisms coupling ceramide to the modulation of the immune response is depicted in Fig. 3 and shows how ceramide may play pivotal roles in regulating a number of complex processes. The SM pathway represents a potentially valuable focal point for therapeutic control of immune responses, perhaps for either enhancement of the activity of T cells in the elimination of tumors, or the down-regulation of lymphocyte function in instances of autoimmune disease. The recent explosion of knowledge regarding ceramide signalling notwithstanding, a number of critical questions need to be answered before a comprehensive, mechanistic understanding can be formulated relative to the incredibly varied effects of ceramide on cell function. For example, (i) how is a structurally simple molecule like ceramide able to mediate so many different, and sometimes paradoxical, physiological responses ranging from cell proliferation and differentiation to inhibition of cell growth and apoptosis, (ii) what are the molecular identities and modes of activation of the various SMase isoforms, (iii) what determines the distribution of the unique isoforms of SMase in cells of different lineages or at different stages of differentiation, (iv) what is the relative contribution of ceramide generated through SM hydrolysis versus de novo synthesis, and (v) by what means does ceramide interact with specific intracellular targets? Although a number of ceramide-activatable kinases, phosphatases, and their protein substrates have been identified, a more extensive search for additional cellular targets will be indispensable in determining the phosphorylation cascades linking the activation of the SM pathway to the regulation of nuclear events. Clearly, cross-talk between ceramide-induced signal transduction cascades and other signalling pathways adds to the inherent difficulty in distinguishing the specific effects of complex, intertwining signalling pathways.
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PMID:Ceramide signalling and the immune response. 866 39

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