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)

Following incubation of murine epidermis in medium containing either interleukin-2 or interleukin-6, there is significant upregulation in the density of Ia+ epidermal Langerhans cells (to 159% and 175% of control, respectively). This cytokine-induced upregulation is abrogated by either rabbit or human IgG due to triggering of Fc gamma receptors. In contrast, human IgA does not inhibit the effect of interleukin-2 or interleukin-6. Using different isotypes of murine IgG, we have demonstrated that all subclasses are capable of inhibiting the cytokine-induced enhancement of Ia antigen, although IgG1 and IgG2b must be heat aggregated to be effective. The IgG-mediated events are dependent on prostaglandin synthesis because they can be blocked by the cyclooxygenase inhibitor indomethacin, 10 micrograms/ml. The responsible PG appears to be PGD2; in contrast to its known inhibitory effect on macrophages, PGE2 does not inhibit the upregulation of Ia antigen on Langerhans cells. In addition, these IgG-mediated events are dependent upon the generation of cAMP because they can be blocked by the adenylate cyclase inhibitor 2',5'-dideoxyadenosine, 1 mM. Despite the apparently central role of PGD2 and cAMP in this process, triggering of the Fc gamma R by different isotypes of IgG blocks upregulation of Ia via at least two different pathways. The inhibition caused by aggregated IgG1 or IgG2b, which bind to Fc gamma RII on Langerhans cells, is abrogated by para-bromophenacylbromide, an inhibitor of phospholipase A2. In contrast, the inhibition caused by monomeric IgG2a, which binds to Fc gamma RI most likely on keratinocytes, or monomeric IgG3, which probably binds to this same Fc gamma RI, is abrogated by staurosporine, an inhibitor of protein kinase C, as well as by W7, a calmodulin antagonist. Finally, 1,2 dioctanoyl-rac-glycerol, an activator of protein kinase C, mimics the Ig-mediated events. Based on these findings, as well as studies using monoclonal antibodies to the murine Fc gamma receptors I and II, we conclude that, as is the case in murine macrophages, triggering of an epidermal Fc gamma RI, most likely on keratinocytes, results in the generation of cAMP via a Ca(++)-dependent protein kinase C pathway, whereas triggering of an epidermal Fc gamma RII, most likely on Langerhans cells, results in the elevation of cAMP via a phospholipase A2-mediated pathway. In contrast to the situation for macrophages, PGD2 is a vital intermediate in both pathways, perhaps because Langerhans cells have receptors for only this prostaglandin.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effect of triggering epidermal Fc gamma receptors on the interleukin-2- and interleukin-6-induced upregulation of Ia antigen expression by murine epidermal Langerhans cells: the role of prostaglandins and cAMP. 165 69

Substance P (SP) and lipopolysaccharide (LPS) stimulated interleukin-6 (IL-6) gene expression, as well as IL-6 protein secretion in the human astrocytoma cell line U373 MG. Staurosporine, an inhibitor of protein kinase C (PKC), entirely blocked SP- but not LPS-induced IL-6 release. In addition, the down regulation of PKC inhibited the SP response and only marginally altered LPS activation. Differently from SP, LPS-induced IL-6 release was markedly reduced by W7, a calmodulin antagonist. Moreover, SP interacted in a synergistic manner with LPS. Thus, neural (SP) and bacterial (LPS) mediators stimulate U373 MG IL-6 release via distinct, though not antagonistic, activation pathways.
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PMID:Interleukin-6 production by U373 MG, a human astrocytoma cell line: different pathways involved in substance P and lipopolysaccharide activation. 754 Oct 52

Interleukin-6 (IL-6) may play an important role in human CG (hCG) production by activating the IL-6-receptor (-R) system on human trophoblasts. Trophoblasts produced hCG in response to rIL-6 as well as to 8-bromo cAMP (8-Br-cAMP), 12-O-tetradecanoyl phorbol-13-acetate (TPA), and calcium ionophore A23187. To determine whether the signal transduction pathway activated by the IL-6-R system depends on protein kinases such as protein kinase A, protein kinase C, and Ca2+/calmodulin-dependent kinase, trophoblasts were stimulated with recombinant (r-) IL-6 in the presence or absence of protein kinase inhibitors such as N(2-methyl-aminoethyl)-5-isoquinoline sulfonamide dihydrochloride (H8), and 1-(5-isoquinolinesulfomyl)-2-methylpiperazine (H7) and a calmodulin antagonist, N-(6-aminohexyl)-5-chloro-1- napthalenesulfonamide (W7), H8, H7, and W7 failed to suppress rIL-6-induced hCG production but completely inhibited hCG production induced by 8-Br-cAMP, TPA, and the GnRH agonist (GnRHa), respectively. In contrast, genistein, a tyrosine kinase inhibitor, completely suppressed rIL-6-induced hCG production but failed to inhibit hCG production induced by 8-Br-cAMP, TPA, and A23187. Genistein also did not suppress GnRH-induced hCG production. The addition of genistein to rIL-1- and rTNF-alpha-stimulated trophoblasts inhibited rIL-1-induced and rTNF-alpha induced hCG production but maintained rIL-1- and rTNF-alpha-induced IL-6 production. These results show that the IL-6/IL-6-R system-induced signal transduction pathway in the placenta probably stimulates hCG production by activating a tyrosine kinase pathway. The experiment with genistein shows that the GnRH/GnRH-R system activates a signal transduction pathway distinct from that activated by the IL-6/IL-6-R system.
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PMID:The interleukin-6 (IL-6)/IL-6-receptor system induces human chorionic gonadotropin production by activating tyrosine kinase-dependent signal transduction pathway different from pathways triggered by protein kinase activators including gonadotropin releasing hormone. 837 Jun 93

Interleukin-6 (IL-6) activation of the immediate-early gene junB has been shown to require both a tyrosine kinase and an unknown 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7)-sensitive pathway. Here we report the identification and characterization of an IL-6 immediate-early response element in the junB promoter (designated JRE-IL6) in HepG2 cells. The JRE-IL6 element, located at -149 to -124, contains two DNA motifs, an Ets-binding site (EBS) (CAGGAAGC) and a CRE-like site (TGACGCGA). Functional studies using variously mutated JRE-IL6 elements showed that both motifs were necessary and sufficient for IL-6 response of the promoter. The EBS of the JRE-IL6 element (JEBS) appears to bind a protein in the Ets family or a related protein which could also form a major complex with the EBSs of the murine sarcoma virus long terminal repeat or human T-cell leukemia virus type 1 long terminal repeat. The CRE-like site appears to weakly bind multiple CREB-ATF family proteins. Despite the similarity in the structure between the JRE-IL6 element and the polyomavirus enhancer PyPEA3, composed of an EBS and an AP1-binding site and known to be activated by a variety of oncogene signals, JRE-IL6 could not be activated by activated Ha-Ras, Raf-1, or 12-O-tetradecanoylphorbol-13-acetate. We show that IL-6 activates JRE-IL6 through an H7-sensitive pathway that does not involve protein kinase C, cyclic AMP-dependent kinase, Ca(2+)- or calmodulin-dependent kinases, Ras, Raf-1, or NF-IL6 (C/EBP beta). The combination of JEBS and the CRE-like site appears to form the basis for the selective and efficient response of JRE-IL6 to IL-6 signals, but not to signals generated by activated Ha-Ras, Raf-1, or protein kinase C.
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PMID:Identification of a novel interleukin-6 response element containing an Ets-binding site and a CRE-like site in the junB promoter. 838 18

This study was designed to determine whether mechanical stretch activates the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway in cardiomyocytes and, if so, by what mechanism. Neonatal rat/murine cardiomyocytes were cultured on malleable silicone dishes and were stretched by 20%. Mechanical stretch induced rapid phosphorylation of JAK1, JAK2, Tyk2, STAT1, STAT3, and glycoprotein 130 as early as 2 minutes and peaked at 5 to 15 minutes. It also caused gel mobility shift of sis-inducing element, which was supershifted by preincubation with anti-STAT3 antibody. Preincubation with CV11974 (AT1 blocker) partially inhibited the phosphorylation of STAT1, but not that of STAT3. Preincubation with TAK044 (endothelin-1-type A/B-receptor blocker) did not attenuate this pathway. RX435 (anti-glycoprotein 130 blocking antibody) inhibited the phosphorylation of STAT3 and partially inhibited that of STAT1. Phosphorylation of STAT1 and STAT3 was strongly inhibited by HOE642 (Na+/H+ exchanger inhibitor) and BAPTA-AM (intracellular calcium chelator), but not by gadolinium (stretch-activated ion channel inhibitor), EGTA (extracellular Ca2+ chelator), or KN62 (Ca2+/calmodulin kinase II inhibitor). Chelerythrine (protein kinase C inhibitor) partially inhibited the phosphorylation of STAT1 and STAT3. Mechanical stretch also augmented the mRNA expression of cardiotrophin-1, interleukin-6, and leukemia inhibitory factor at 60 to 120 minutes. These results indicated that the JAK/STAT pathway was activated by mechanical stretch, and that this activation was partially dependent on autocrine/paracrine-secreted angiotensin II and was mainly dependent on the interleukin-6 family of cytokines but was independent of endothelin-1. Moreover, certain levels of intracellular Ca2+ were necessary for stretch-induced activation of this pathway, and protein kinase C was also partially involved in this activation.
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PMID:Mechanical stretch activates the JAK/STAT pathway in rat cardiomyocytes. 1034 87

Bradykinin, a mediator of inflammation, is produced in the brain during trauma and stroke. It is thought to open the blood-brain barrier, although the mechanism is unclear. We have investigated, therefore, the effect of bradykinin on the expression of interleukin-6 (IL-6), a putative modulator of the blood-brain barrier, in astrocytes. IL-6 gene transcription was evaluated by transient transfection of the human IL-6 promoter linked to the luciferase gene. In murine astrocytes, bradykinin stimulated IL-6 secretion and gene transcription. The effect of bradykinin was blocked by KN-93, an inhibitor of Ca2+/calmodulin-dependent protein kinases, and by bisindolylmaleimide I, an inhibitor of protein kinase C, suggesting the involvement of these protein kinases. Mutations in the multiple response element and the binding site for nuclear factor-kappaB (NF-kappaB), but not in other known elements of the IL-6 promoter, interfered with induction of IL-6 transcription. The involvement of NF-kappaB was supported further by the finding that overexpression of nmIkappaB alpha, a stable inhibitor of NF-kappaB, inhibited the induction of IL-6 by bradykinin. Bradykinin activated NF-kappaB in primary astrocytes as shown by increased DNA binding of NF-kappaB. These data demonstrate that bradykinin stimulates IL-6 expression through activation of NF-kappaB, which may explain several inflammatory effects of bradykinin.
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PMID:Bradykinin induces interleukin-6 expression in astrocytes through activation of nuclear factor-kappaB. 1050 Nov 90

Our previous study has demonstrated the potentiation by uridine triphosphate (UTP) of nitric oxide (NO) and prostaglandin E(2) (PGE(2)) production in lipopolysaccharide (LPS)-stimulated murine J774 macrophages. In this study, we found that the amount of interleukin-6 (IL-6) release in response to LPS stimulation was greatly enhanced in the presence of UTP. This enhancement exhibited concentration dependence and occurred after 8 h of treatment with LPS. RT-PCR analysis indicated that the steady-state level of IL-6 mRNA induced by LPS was apparently increased upon co-addition of UTP. The potentiation by UTP was inhibited by the treatment with U73122 (a phosphatidylinositol-phospholipase C inhibitor), BAPTA/AM (an intracellular Ca(2+) chelator), KN-93 (a selective inhibitor of calmodulin-dependent protein kinase) or PDTC (a nuclear factor kappaB inhibitor). To understand the cross-regulation among NO, PGE(2) and IL-6, all of which are dramatically induced after LPS stimulation, the effects of L-NAME (a nitric oxide synthase inhibitor), indomethacin (a cyclooxygenase inhibitor), NS-398 (a cycloxygenase-2 inhibitor) and IL-6 antibody were tested. The results revealed the positive regulation between PGE(2) and IL-6 synthesis because NS-398 and indomethacin inhibited LPS plus UTP-induced IL-6 release, and IL-6 antibody attenuated LPS plus UTP-induced PGE(2) release. Taken together these results reinforce the role of UTP as a regulatory element in inflamed sites by demonstrating the capacity of this nucleotide to potentiate LPS-induced release of inflammatory mediators.
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PMID:Potentiation of lipopolysaccharide-induced IL-6 release by uridine triphosphate in macrophages: cross-interaction with cyclooxygenase-2-dependent prostaglandin E(2) production. 1054 78

We previously reported that ganglioside GD1a greatly enhanced spontaneous immunoglobulin (Ig) production by human peripheral blood mononuclear cells (PBMC) in vitro. We herein examined the mechanism for the stimulatory effect of GD1a.PBMC from healthy volunteers were cultured with GD1a. The amounts of IgG, IgM, and IgA and cytokine activity in the culture supernatants were measured by enzyme-linked immunosorbent assays. Proliferation was determined by [3H] thymidine uptake.GD1a at 10(-6) M increased IgG, IgM, and IgA production by PBMC 2.10-fold, 2.10-fold, and 2.23-fold above the control values, respectively. GD1a did not affect the proliferation and viability of PBMC. GD1a did not alter Ig production of B cells alone. Anti-interleukin-6 (IL-6) or anti-IL-10 antibody each partially blocked the GD1a-induced enhancement of Ig production by PBMC, and the addition of both antibodies completely blocked the enhancement. GD1a increased IL-6 and IL-10 production of monocytes without altering those of T cells or B cells. The supernatant from GD1a-treated monocytes enhanced B cell Ig production to a greater extent than that from medium-treated monocytes. The supernatant-mediated effect of GD1a was partially blocked by anti-IL-6 or anti-IL-10 antibody, and the addition of both antibodies completely blocked the GD1a effect. GD1a-induced increases of IL-6 and IL-10 production in monocytes were both blocked by Ca(2)+/calmodulin (CaM)-dependent phosphodiesterase (PDE) inhibitors, 8-methoxymethyl-3-isobutyl-1-methylxanthine and vinpocetin, but not by other signal-transducing enzyme inhibitors. The culture with GD1a enhanced Ca(2)+/CaM-dependent PDE activity in monocytes. These results suggest that GD1a may indirectly enhance B cell Ig production in whole PBMC by increasing IL-6 and IL-10 production of monocytes via promoting Ca(2)+/CaM-dependent PDE activity.
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PMID:Ganglioside GD1a enhances immunoglobulin production by human peripheral blood mononuclear cells. 1088 Jul 53

Interleukin-6 (IL-6) has neuromodulatory and neuroprotective effects in vivo. It is expressed in glial cells and neurons both under physiological conditions and in various neurological diseases. Although the expression of IL-6 in glia has been intensely investigated, little is known about the regulation of IL-6 production by neurons. Therefore, we investigated the regulation of IL-6 expression in neurons. Membrane depolarization raised IL-6 mRNA accumulation in primary cortical cells and the PC-12 cell line. In vivo, IL-6 mRNA in the brain increased significantly after epileptic seizures. To investigate IL-6 gene transcription, PC-12 cells were transfected with reporter gene constructs containing the human IL-6 promoter. Membrane depolarization raised IL-6 transcription twofold to fourfold. This increase could be blocked by lowering extracellular Ca(2+) levels or by inhibiting L-type Ca(2+) channels or Ca(2+)/calmodulin-dependent protein kinases. Internal mutations in various elements of the IL-6 promoter revealed the glucocorticoid response element (GRE) 2 to be a depolarization-responsive element. Although the GRE2 bound the glucocorticoid receptor (GR) and was stimulated by dexamethasone, the GR was not responsible for the effect of membrane depolarization because a consensus GRE did not mediate stimulation by membrane depolarization. Instead, another yet undefined factor that binds to the IL-6 GRE2 may mediate the response to membrane depolarization. These data demonstrate that the expression of IL-6 in neurons is regulated by membrane depolarization and suggest a novel Ca(2+)-responsive promoter element. Through this mechanism, IL-6 may function as a neuromodulator induced by neuronal activity.
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PMID:Induction of interleukin-6 by depolarization of neurons. 1110 68

Leptin, an adipocytokine encoded by an obesity gene and expressed in adipose tissue, affects feeding behavior, thermogenesis, and neuroendocrine status via leptin receptors distributed in the brain, especially in the hypothalamus. Leptin may also modulate the synaptic plasticity and behavioral performance related to learning and memory since: leptin receptors are found in the hippocampus, and both leptin and its receptor share structural and functional similarities with the interleukin-6 family of cytokines that modulate long-term potentiation (LTP) in the hippocampus. We therefore examined the effect of leptin on (1) behavioral performance in emotional and spatial learning tasks, (2) LTP at Schaffer collateral-CA1 synapses, (3) presynaptic and postsynaptic activities in hippocampal CA1 neurons, (4) the intracellular Ca(2+) concentration ([Ca(2+)](i)) in CA1 neurons, and (5) the activity of Ca(2+)/calmodulin protein kinase II (CaMK II) in the hippocampal CA1 tissue that exhibits LTP. Intravenous injection of 5 and/or 50mug/kg, but not of 500mug/kg leptin, facilitated behavioral performance in passive avoidance and Morris water-maze tasks. Bath application of 10(-12)M leptin in slice experiments enhanced LTP and increased the presynaptic transmitter release, whereas 10(-10)M leptin suppressed LTP and reduced the postsynaptic receptor sensitivity to N-methyl-d-aspartic acid. The increase in the [Ca(2+)](i) induced by 10(-10)M leptin was two times greater than that induced by 10(-12)M leptin. In addition, the facilitation (10(-12)M) and suppression (10(-10)M) of LTP by leptin was closely associated with an increase and decrease in Ca(2+)-independent activity of CaMK II. Our results show that leptin not only affects hypothalamic functions (such as feeding, thermogenesis, and neuroendocrine status), but also modulates higher nervous functions, such as the behavioral performance related to learning and memory and hippocampal synaptic plasticity.
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PMID:Leptin facilitates learning and memory performance and enhances hippocampal CA1 long-term potentiation and CaMK II phosphorylation in rats. 1691 28


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