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)

The cytokine interleukin-6 (IL-6) is increased in bone and bone cells by several resorptive stimuli, including parathyroid hormone (PTH), IL-1beta, and tumor necrosis factor-alpha (TNF-alpha). The current studies were designed to determine the contribution of the protein kinase C (PKC) signaling pathway to the effects of these three agents to increase IL-6 in UMR-106 rat osteoblastic cells. Cells were pretreated with vehicle (dimethylsulfoxide [DMSO]) or the phorbol ester, phorbol 12,13-dibutyrate (PDB; 300 nM) for 48 h to down-regulate phorbol-sensitive PKC isozymes. Either PTH (0.1-10 nM), IL-1beta (0.1-10 nM), or TNF-alpha (5 nM and 10 nM) was then added for 24 h in the continued presence of vehicle or PDB. PKC isozymes were visualized by Western immunoblotting and IL-6 was determined by bioassay. PDB pretreatment caused a partial down-regulation of the conventional alpha-PKC and betaI-PKC isozymes and complete down-regulation of the novel delta-isoenzyme and epsilon-isozymes but it had no effect on the atypical zeta-PKC isozyme. PDB pretreatment reduced IL-6 responses to 5 nM and 10 nM PTH by 61% and 33%, respectively, reduced IL-6 responses to 5nM and 10 nM TNF-a by 54% and 42%, respectively, and failed to inhibit the IL-6 responses to 0.1-10 nM IL-1beta. The PDB pretreatment protocol significantly enhanced PTH-stimulated cyclic adenosine monophosphate (cAMP) production. The PKC inhibitor calphostin C also decreased IL-6 responses to PTH. Thus, in this osteoblast cell line, the PKC pathway is an important component of the signaling pathway for the IL-6 production stimulated by PTH and TNF-alpha but not that from IL-1beta.
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PMID:Protein kinase C involvement in interleukin-6 production by parathyroid hormone and tumor necrosis factor-alpha in UMR-106 osteoblastic cells. 1080 18

Epinephrine increased gene- and protein-expression of interleukin-6 (IL-6) and interleukin-11 (IL-11), which are capable of stimulating the development of osteoclasts from their hematopoietic precursors, in human osteoblast (SaM-1) and human osteosarcoma (SaOS-2, HOS, and MG-63) cell lines. An increase in IL-6 and IL-11 synthesis in response to epinephrine appeared to be a common feature in osteoblastic cells, but the magnitude of expression was different in these cell lines. In HOS cells treated with epinephrine, increases of IL-6 and IL-11 synthesis were inhibited by timolol (a beta-blocker), H-89 (N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide; an inhibitor of protein kinase A (PKA)) and SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole; an inhibitor of p38 mitogen-activated protein kinase (MAPK)], but not by phentolamine (an alpha-blocker), calphostin C [an inhibitor of protein kinase C (PKC)], or PD98059 (2'-amino-3'-methoxyflavone; an inhibitor of classic MAPK), suggesting a common pathway mediated by beta-adrenergic receptors in the PKA and p38 systems involved in the signal transduction of IL-6 and IL-11. Furthermore, expression of both genes was inhibited by curcumin [an inhibitor of activating protein-1 (AP-1) activation], but not by pyrrolidine dithiocarbamate (PDTC) [an inhibitor of nuclear factor (NF)-kappaB]. The pharmacological study suggested that coinduction of the two genes in response to epinephrine occurred via activation of AP-1. The findings of the present study suggest that coinduction of IL-6 and IL-11 in response to epinephrine probably occurs via the PKA and p38 MAPK systems, leading to the transcriptional activation of AP-1 in human osteoblastic cells.
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PMID:Signal transduction system for interleukin-6 and interleukin-11 synthesis stimulated by epinephrine in human osteoblasts and human osteogenic sarcoma cells. 1117 36

Alcoholics frequently suffer from moderate to severe bone loss that results in bone fractures. Both decreased bone production and increased bone resorption have been postulated to contribute to ethanol (ETOH)-mediated bone loss. Bone resorption is induced by several proinflammatory cytokines such as interleukin-1 and -6. The expression of these cytokines is induced by the transcription factor NFkappaB, which, in turn, is activated by several kinases. It follows that protein kinase and NFkappaB activation may contribute to ETOH-induced bone loss. Accordingly, we sought to determine if ETOH activates protein tyrosine kinases (PTK) and NFkappaB DNA binding in a human osteoblast-like cell line (HOBIT). Ethanol at 50 and 100 mmol/L (reflective of blood ethanol levels reached in chronic alcoholics) for 24 h did not alter HOBIT cell viability. In contrast, 200 mmol/L ethanol decreased cell viability by 40%. Treatment of HOBIT cells with 100 mmol/L ETOH induced nuclear NFkappaB:DNA complex formation and NFkappaB activity. Incubation of HOBIT cells with ETOH at 50 and 100 mmol/L for 30 min induced a 2.5- and 4.2-fold increase in PTK activity, respectively. Preincubation of HOBIT cells with damnacanthal (DAM), which inhibits p56lck, blocked ETOH-mediated PTK activity; whereas, preincubation with herbimycin A, which inhibits pp60src, did not. DAM inhibited both ethanol-induced NFkappaB activation in HOBIT cells and interleukin-6 expression in primary human osteoblasts. Finally, preincubation with the protein kinase C inhibitor, bisindolylmaleimide I HCl (BIS), diminished ETOH-mediated PTK activity; whereas, preincubation with the protein kinase A inhibitor, H89, did not. These data demonstrate that ETOH induces NFkappaB nuclear translocation through p56lck in HOBIT cells. BIS' inhibition of PTK activation suggests that ETOH activates PTK through a protein kinase C-dependent pathway. These data suggest that ETOH may contribute to bone loss through activation of signal transduction that results in production of an osteoclastogenic cytokine (i.e., interleukin-6) in osteoblasts.
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PMID:Ethanol activates NFkappaB DNA binding and p56lck protein tyrosine kinase in human osteoblast-like cells. 1118 74

Prostaglandins (PG) E1, E2 and F2alpha induce bone resorption in isolated neonatal parietal bone cultures, and an associated increase in interleukin-6 (IL-6) production. Indomethacin had little effect on the response to PGE2, or the relatively non-selective EP receptor agonists 11-deoxy PGE1 and misoprostol, but blocked the effects of PGF2alpha and the F receptor agonist fluprostenol, indicating an indirect action via release of other prostaglandins. It is more likely that there is positive autoregulation of prostaglandins production in this preparation mediated via stimulation of F receptors. The effects of selective EP receptor agonists sulprostone (EP1,3) and 17-phenyl trinor PGE2(EP1), indicated the involvement of EP2 and/or EP4 receptors, which signal via cAMP. The relatively weak increase in IL-6 production by misoprostol (with respect to resorption) suggests that these responses are controlled by different combination of EP2 and EP4 receptors. The PKA activator, forskolin, induced small increases in bone resorption at lower concentrations (50-500 ng/ml) but a reversal of this effect, and inhibition of resorption induced by other stimuli (PTH, PGE2), at higher concentrations (0.5-5 microg/ml). IL-6 production was markedly increased only at the higher concentrations. The inhibitory effect of forskolin may be a calcitonin-mimetic effect. PMA induced both resorption and IL-6 production which were both blocked by indomethacin, indicating a role for PKC in the control of prostaglandin production.
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PMID:Mechanisms involved in prostaglandin-induced increase in bone resorption in neonatal mouse calvaria. 1123 79

Interleukin-6 (IL-6) is a B-cell differentiating and T-cell activating cytokine that is expressed in T cells, neutrophils, monocytes, macrophages, and mast cells. Because IL-6 is also synthesized and released by anterior pituitary cells and IL-6 stimulates pituitary hormone release, this cytokine may serve a paracrine or autocrine role within the pituitary. Interleukin-1 beta (IL-1 beta) stimulates IL-6 release from anterior pituitary cells through a mechanism that involves lysophosphatidylcholine (LPC 18:0) generation and protein kinase C activation. In the rat C6 glioma cell line, IL-1 beta synergistically stimulates IL-6 release in the presence of increased intracellular cAMP concentrations. The catecholamines and serotonin also synergistically stimulate IL-6 release in the presence of IL-1 beta. LPC 18:0 synergistically increases IL-6 release in the presence of norepinephrine, and IL-1 beta transiently increases LPC 18:0 formation in C6 cells. Therefore, IL-1 beta induction of LPC 18:0 may lead to increases in IL-6 production via activation of a kinase cascade. The bovine thymic preparation, thymosin fraction 5 (TF5), also stimulates IL-6 release from C6 glioma cells in a protein kinase C-dependent manner. Of interest, TF5 inhibits the proliferation of C6 cells, pituitary adenoma MMQ cells, and promyelocytic HL-60 cells. We suggest that a thymic hormone immune surveillance mechanism may suppress neuroendocrine and hematopoietic tumor formation. Thus, IL-1 beta and certain thymic peptides act to increase IL-6 expression in neuroendocrine cells. The enhanced production of neuroendocrine cytokines may affect hormone secretion, neurotransmission, and the development of certain neurodegenerative disorders (e.g., Alzheimer's disease). The isolation of the active component of TF5 that inhibits neuroendocrine and hematopoietic tumor cell proliferation will provide a potential therapeutic strategy for the treatment of these tumors.
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PMID:Interleukin-1 beta and thymic peptide regulation of pituitary and glial cell cytokine expression and cellular proliferation. 1126 88

We have explored the regulatory roles played by Ca2+-dependent signaling on lipopolysaccharide (LPS)-induced nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor alpha (TNF-alpha), and interleukin-6 (IL-6) release in mouse peritoneal macrophages. To elevate intracellular Ca2+, we used thapsigargin (TG) and UTP. Although LPS alone cannot stimulate NO synthesis, co-addition with TG, which sustainably increased [Ca2+]i, resulted in NO release. UTP, via acting on P2Y6 receptors, can stimulate phosphoinositide (PI) turnover and transient [Ca2+]i increase, however, it did not possess the NO priming effect. LPS alone triggered the release of PGE2, TNF-alpha, and IL-6; all of which were potentiated by the presence of TG, but not of UTP. The stimulatory effect of LPS plus TG on NO release was inhibited by the presence of Ro 31-8220, Go6976, KN-93, PD 098059, or SB 203580, and abolished by BAPTA/AM and nuclear factor kappaB (NF-kappaB) inhibitor, PDTC. PGE2, TNF-alpha, and IL-6 release by LPS alone were attenuated by Ro 31-8220, Go6976, PD 098059, SB 203580, and PDTC. Using L-NAME, soluble TNF-alpha receptor, IL-6 antibody, NS-398, and indomethacin, we performed experiments to understand the cross-regulation by the four mediators. The results revealed that TNF-alpha up-regulated NO, PGE2, and IL-6 synthesis; PGE2 up-regulated NO, but down-regulated TNF-alpha synthesis; and PGE2 and IL-6 mutually up-regulated reciprocally. Taken together, murine peritoneal macrophages required a sustained [Ca2+]i increase, which proceeds after TG, but not UTP, stimulation, to enhance LPS-mediated release of inflammatory mediators, particularly for NO induction. Activation of PKC-, ERK-, and p38 MAPK-dependent signaling also are essential for LPS action. The positive regulatory interactions among these mediators might amplify the inflammatory response caused by endotoxin.
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PMID:Involvement of protein kinases in the potentiation of lipopolysaccharide-induced inflammatory mediator formation by thapsigargin in peritoneal macrophages. 1127 79

Glial cells release neurotrophic factors that maintain neurons functionally. Previously, we have shown that the scabronines isolated from Sarcodon scabrosus enhanced the secretion of neurotrophic factors from 1321N1 human astrocytoma cells. In the present study, we examined the mechanism of newly synthesized scabronine G-methylester (ME)-induced secretion of neurotrophic factors from 1321N1 cells. The dramatic neuronal differentiation of rat pheochromocytoma cells (PC-12) was observed by scabronine G-ME-conditioned medium of 1321N1 cells. Scabronine G-ME increased the secretion of nerve growth factor (NGF) and interleukin-6 (IL-6) from 1321N1 cells with the enhancement of their mRNA expressions. Scabronine G-ME concentration-dependently inhibited the carbachol-induced inositol phosphate accumulation in 1321N1 cells, which was reversed by GF109203X, an inhibitor of protein kinase C (PKC) isoforms. Furthermore, GF109203X inhibited the scabronine G-ME-induced mRNA expressions of both NGF and IL-6 and the differentiation of PC-12 cells, showing that scabronine G-ME activated PKC. Although scabronine G-ME enhanced activities of neither conventional nor novel types of PKCs, it translocated PKC-zeta to membranes in intact cells and cell-free condition. Furthermore, recombinant PKC-zeta activity was also increased by scabronine G-ME, suggesting the involvement of PKC-zeta in the effect of scabronine G-ME. Concerning the downstream effectors of the PKC-zeta, scabronine G-ME translocated nuclear factor-kappaB to nucleus, and enhanced its transcriptional activity. In addition, scabronine G-ME caused the degradation of inhibitor of nuclear factor-kappaB concentration-dependently, which was inhibited by GF109203X. These results suggest that scabronine G-ME potentially enhances the secretion of neurotrophic factors from 1321N1 cells mediated via the activation of PKC-zeta.
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PMID:Scabronine G-methylester enhances secretion of neurotrophic factors mediated by an activation of protein kinase C-zeta. 1130 14

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).
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PMID:Interleukin-6 increases the survival of retinal ganglion cells in vitro. 1143 Oct 3

To investigate the level at which protein kinase C (PKC) regulates expression of interleukin-6 (IL-6) in osteoblastic cells, effects of several PKC antagonists and PKC down-regulation by phorbol ester were studied in UMR-106 osteoblastic cells that had been transiently transfected with a -224/+11-base pair (bp) IL-6 promoter coupled to a luciferase reporter. Parathyroid hormone (PTH) elicited a dose-dependent stimulation of the IL-6 promoter expression, with significant increases produced by 5 h of treatment with concentrations of PTH as low as 10(-14) M. The increase in IL-6 promoter expression was inhibited by the PKC antagonists GF109203X, 30 nM to 1 microM, and calphostin C, 250 nM. Prior down-regulation of PKC with 100 nM phorbol-12,13-dibutyrate (PDBU) for 48 h inhibited the PTH effect as well as the smaller stimulatory effects elicited by tumor necrosis factor alpha (TNF-alpha), 10(-9)-10(-8) M, and by IL-1beta, 1-10 ng/ml. In contrast to these findings, the stimulatory effects of PTH, TNF-alpha, and IL-1beta on the IL-6 promoter expression were enhanced by staurosporine. Treatment with GF109203X or down-regulation of PKC with PDBU prevented the stimulatory effects of staurosporine. PKC activity was increased by staurosporine. The findings with staurosporine are consistent with our earlier observations that this agent enhances the calcium signaling and bone resorption elicited by PTH. The studies support the role of PKC in the stimulatory effects of PTH, TNF-alpha, and IL-1beta on IL-6 expression.
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PMID:Stimulation of interleukin-6 promoter by parathyroid hormone, tumor necrosis factor alpha, and interleukin-1beta in UMR-106 osteoblastic cells is inhibited by protein kinase C antagonists. 1145 Jun 97

It has been demonstrated that calcitonin-binding sites are present in a variety of tissue types, including in the pituitary gland. Interleukin-6 (IL-6) is also produced in the pituitary and it regulates the secretion of various hormones. In this study, we examined the expression of the calcitonin receptor and the mechanism of IL-6 production induced by calcitonin in the pituitary folliculo-stellate cell line (TtT/GF). The mRNA of calcitonin receptor subtype C1a, but not that of C1b, was detected by RT-PCR in TtT/GF cells and in the normal mouse pituitary. Calcitonin increased cAMP accumulation and IL-6 production in a concentration-dependent manner in TtT/GF cells. As calcitonin activates the PKA and PKC pathways, we investigated the contributions of PKA and PKC to IL-6 production. IL-6 production was only slightly increased by either 8-bromo-cAMP (1 mM) or phorbol 12-myristate 13-acetate (100 nM) alone. However, IL-6 was synergistically induced in the presence of both 8-bromo-cAMP (1 mM) and phorbol 12myristate 13-acetate (100 nM). Furthermore, calcitonin-induced IL-6 production was completely suppressed by H-89 (PKA inhibitor) or GF109203X (PKC inhibitor), indicating that the activation of both PKA and PKC is necessary for calcitonin-induced IL-6 production. On the other hand, pertussis toxin (G(i)/G(o) signaling inhibitor) treatment achieved an approximately 9-fold increase in calcitonin-induced IL-6 production. These results show that calcitonin-stimulated IL-6 production is mediated via both PKA- and PKC-signaling pathways, whereas calcitonin also suppresses IL-6 production by activating G(i)/G(o) proteins in folliculo-stellate cells.
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PMID:Calcitonin induces IL-6 production via both PKA and PKC pathways in the pituitary folliculo-stellate cell line. 1145 4

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