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)

In contrast to the intensively studied nerve growth factor (NGF)-related family of cytokines, relatively little is known about the mechanisms of neurotrophic activity elicited by the cytokine interleukin-6 (IL-6). We have examined the mechanisms of IL-6-induced neuronal differentiation of the pheochromocytoma cell line PC12. IL-6 independently induced the expression of peripherin, identifying this gene as the first neuronal-specific target of IL-6. However, IL-6 alone failed to elicit neurite outgrowth in PC12 cells and instead required low levels of Trk/NGF receptor tyrosine kinase activity to induce neuronal differentiation. The cooperating Trk signal could be provided by either overexpression of Trk or exposure to low concentrations of NGF. IL-6 also functioned cooperatively with basic fibroblast growth factor to promote PC12 differentiation. IL-6 and Trk/NGF synergized in enhancing tyrosine phosphorylation of the Erk-1 mitogen-activated protein kinase and in activating expression of certain NGF target genes. NGF also induced expression of the gp80 subunit of the IL-6 receptor, providing another potential mechanism of cooperativity between NGF and IL-6 signaling. We propose that IL-6 functions as an enhancer of NGF signaling rather than as an autonomous neuronal differentiation signal. Moreover, our results demonstrate that a Trk receptor-specific cellular response can be achieved in the absence of NGF through amplification of its basal signaling activity by the IL-6 receptor system.
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PMID:Interleukin-6 induces expression of peripherin and cooperates with Trk receptor signaling to promote neuronal differentiation in PC12 cells. 885 17

Cytokines are a group of secreted proteins that exhibit diverse biological activity and are especially important in immune and inflammatory responses. The inappropriate production of cytokines in the central nervous system (CNS) has been implicated in a number of disease states such as Alzheimer's disease, multiple sclerosis, and AIDS dementia complex. This article focuses on the biological role of three cytokines in the CNS, interleukin-6 (IL-6), tumor necrosis factor alpha, and nerve growth factor, with an emphasis on production by glial cells. We will discuss the diverse intracellular signaling pathways that regulate expression of these cytokines by glial cells and then describe the second messenger systems that mediate cytokine-induced responses in the CNS, with an emphasis on adhesion molecule expression. We conclude by discussing the complexities of signal transduction pathways, particularly "cross-talk" between different intracellular mediators.
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PMID:Second messenger systems in the regulation of cytokines and adhesion molecules in the central nervous system. 890 48

Olfactory neuroepithelial cells (ONC) grown from biopsies of human donors are a novel cell culture system that may facilitate studies into normal and disease-related human neurobiology. We further characterized the expression of cell surface markers and intermediate filaments, and responses to neurotrophic factors by ONC. ONC are positive for cell surface markers N-CAM, PSA-N-CAM, neutral endopeptidase, N-aminopeptidase, NGF low-affinity receptor homologue (CD40), and transferrin receptor by flow cytometry for the intermediate filament proteins peripherin, vimentin, and NF-H by immunocytochemistry. Responses to neurotrophic factors measured were process outgrowth, cytoskeletal protein expression, and protein phosphorylation. Process outgrowth was increased by interleukin-beta 164-171 (IL-1beta) or by the combination of IL-1beta, interleukin-6 (IL-6), nerve growth factor (NGF), and basic fibroblast growth factor (bFGF). This combination of IL-1beta, IL-6, NGF, and bFGF (16NF) increased expression of two cytoskeletal proteins, NF-H protein and microtubule-associated protein tau. Application of the individual neurotrophic factors IL-1beta, IL-6, NGF, and bFGF increased protein phosphorylation, while 16NF produced an immediate increase in tyrosine phosphorylation of several proteins (MW of 40-80, 120, 150, and 190 kDa). The 16NF combination appears to act through a tyrosine-kinase-mediated pathway to induce process extension and increase NF-H expression. The ONC culture has the potential to be further explored to examine the relationship among process outgrowth, protein phosphorylation, and synergy between neurotrophin and cytokine receptor systems.
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PMID:Human olfactory neuroepithelial cells: tyrosine phosphorylation and process extension are increased by the combination of IL-1beta, IL-6, NGF, and bFGF. 891 9

Sciatic sensory afferents that retrogradely transport and accumulate leukaemia inhibitory factor (LIF) within their soma were characterized in the adult rat in vivo. Twenty-four percent of neurons within the L4 and L5 dorsal root ganglia accumulated biotinylated LIF following intraneural injection of the cytokine into the sciatic nerve. Labelled cell bodies were predominantly of small diameter (20.1 +/- 0.5 microm). Retrograde transport was eliminated by excess unlabelled LIF but not by the related cytokines, ciliary-derived neurotrophic factor (CNTF) and interleukin-6 (IL-6). Double labelling revealed that the majority (81%) of LIF-accumulating neurons were immunopositive for CGRP and 34% were immunopositive for the cell surface glycoconjugate IB4. Sixty-two percent of LIF-accumulating neurons were immunopositive for trkA. Our results demonstrate a group of small-diameter sensory neurons that retrogradely transport LIF, comprising cells that constitutively express neuropeptides and those likely to be peptide-deficient. LIF-accumulating neurons expressing trkA are also potentially responsive to nerve growth factor. It is likely that the LIF-accumulating neurons described in this study are nociceptive in function.
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PMID:Leukaemia inhibitory factor is retrogradely transported by a distinct population of adult rat sensory neurons: co-localization with trkA and other neurochemical markers. 921 8

Epidermal Langerhans cells are frequently anatomically associated with calcitonin gene-related peptide-containing nerves. Furthermore, calcitonin gene-related peptide inhibits Langerhans cells antigen-presenting function in several assays. Studies were performed to further explore the hypothesis that Langerhans cells and nerves have a functional relationship. To examine whether Langerhans cells may produce factors that influence nerve cell differentiation, we utilized the Langerhans cell-like cell line XS52 as a surrogate for Langerhans cells and compared it with Langerhans cells enriched to 90%. Supernatants conditioned by lipopolysaccharide-stimulated XS52 cells were able to induce the differentiation of the pheochromocytoma line PC12 into sympathetic neuron-like cells. This was also the case with enriched Langerhans cells stimulated by lipopolysaccharide. Pretreatment of conditioned supernatants with specific neutralizing anti-sera indicated that most of the differentiation-inducing activity was due to interleukin-6 and a small amount was due to nerve growth factor and basic fibroblast growth factor. By reverse transcriptase polymerase chain reaction, three clones of the XS52 cell line, XS52-4D, XS52-11D, and XS52-8B, were found to express mRNA for interleukin-6 and expression was markedly augmented by lipopolysaccharide. mRNA for nerve growth factor and basic fibroblast growth factor was detected in XS52-4D and XS52-11D, but not in XS52-8B. The expression of these neurotrophic factors by enriched Langerhans cells was quite similar to that of XS52-4D. In order to examine whether Langerhans cells may express receptors for nerve-derived peptides, reverse transcriptase polymerase chain reaction was employed to look for pituitary adenylate cyclase activating polypeptide type I, type II, and type III, and gastrin-releasing peptide receptors. All clones examined, as well as enriched Langerhans cells, expressed pituitary adenylate cyclase activating polypeptide type II and type III, and gastrin-releasing peptide receptors. These results suggest bi-directional signalling between Langerhans cells and nerves; nerve cells may regulate Langerhans cell function by elaboration of certain neuropeptides whereas Langerhans cells may promote the differentation of nerves by elaboration of interleukin-6 and, possibly, other factors.
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PMID:Expression of neurotrophic factors and neuropeptide receptors by Langerhans cells and the Langerhans cell-like cell line XS52: further support for a functional relationship between Langerhans cells and epidermal nerves. 932 95

Proinflammatory cytokines are implicated as effector molecules in the pathogenesis of IDDM. Interleukin-6 (IL-6) alone or in combination with IL-1beta inhibits glucose-stimulated insulin release from isolated rat pancreatic islets by unknown mechanisms. Here we investigated 1) if the effects of IL-6 are mimicked by ciliary neurotrophic factor (CNTF), another member of the IL-6 family of cytokines signaling via gp130, 2) the possible cellular mechanisms for these effects, and 3) if islet endocrine cells are a source of CNTF. CNTF (20 ng/ml) potentiated IL-1beta-mediated (5-150 pg/ml) nitric oxide (NO) synthesis from neonatal Wistar rat islets by 31-116%, inhibition of accumulated insulin release by 34-49%, and inhibition insulin response to a 2-h glucose challenge by 31-36%. CNTF potentiated IL-1beta-mediated NO synthesis from RIN-5AH cells by 83%, and IL-1beta induced islet inducible NO-synthase (iNOS) mRNA expression fourfold. IL-6 (10 ng/ml) also potentiated IL-1beta-mediated NO synthesis and inhibition of insulin release, whereas beta-nerve growth factor (NGF) (5 or 50 ng/ml) had no effect. mRNA for CNTF was expressed in rat islets and in islet cell lines. In conclusion, CNTF is constitutively expressed in pancreatic beta-cells and potentiates the beta-cell inhibitory effect of IL-1beta in association with increased iNOS expression and NO synthesis, an effect shared by IL-6 but not by beta-NGF. These findings indicate that signaling via gp130 influences islet NO synthesis associated with iNOS expression. We hypothesize that CNTF released from destroyed beta-cells during the inflammatory islet lesion leading to IDDM may potentiate IL-1beta action on the beta-cells.
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PMID:Ciliary neurotrophic factor potentiates the beta-cell inhibitory effect of IL-1beta in rat pancreatic islets associated with increased nitric oxide synthesis and increased expression of inducible nitric oxide synthase. 975 98

We investigated putative roles of transforming growth factor (TGF)-beta expressed in peripheral ganglia in the regulation of neuronal cell survival during the period of ontogenetic neuron death (OD). The chick ciliary ganglion (CG), where OD occurs between embryonic days (E) 6 and 10, was employed as a model system. We show that CG neurons (E8) are immunoreactive (ir) for TGF-beta2 and -beta3 as well as the TGF-beta receptor TbetaR-II, but are not ir for TGF-beta1. Ciliary neurotrophic factor (CNTF) and fibroblast growth factor (FGF)-2, established neurotrophic molecules for CG neurons, up-regulate TGF-beta3 mRNA and TGF-beta biological activity in cultures of E8 CG neurons. None of the TGF-beta isoforms--beta1, beta2, or beta3--has a trophic, survival-promoting effect on cultured CG neurons. However, all isoforms enhance CG neuron survival mediated by CNTF or FGF-2, significantly and over a wide range of concentrations. In combination with the neurotrophins (NT) nerve growth factor (NGF) and NT-3, which are not neurotrophic for CG neurons, TGF-beta significantly promotes CG neuron survival. However, TGF-beta does not act synergistically with the neuropoietic cytokines oncostatin M, leukemia inhibiting factor, or interleukin-6. Immunoneutralization of endogenous TGF-beta released from CG neurons using an antibody to TGF-beta1/-beta2/-beta3 significantly reduces the potency of CNTF or FGF-2 to promote CG neuron survival. The blocking effect of the anti-pan-TGF-beta antibody could be rescued by adding exogenous TGF-beta. Together, these data suggest that para-/autocrine TGF-beta signaling has an important effect on the regulation of neuron survival in a model system of peripheral neurons.
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PMID:TGF-beta regulates the survival of ciliary ganglionic neurons synergistically with ciliary neurotrophic factor and neurotrophins. 985 58

We investigated a possible link between galanin expression and evoked pain accompanying painful partial sciatic nerve lesions. Increased galanin immunoreactivity (IR) in the dorsal horn, in gracile nucleus, and in sensory neurons following chronic constriction injury (CCI) compared to complete sciatic transection suggested a facilitatory role in thermal and mechanical hypersensitivity (allodynia). We therefore investigated the effects of endogenous interleukin-6 (IL-6) and nerve growth factor (NGF) on allodynia and neuropeptide expression. IL-6 knockout mice showed decreased allodynia and galanin-IR compared to wild-type mice, but also decreased substance P (SP)-IR in the dorsal horn. Anti-NGF-treated rats with CCI also showed decreased allodynia and SP-IR, but increased galanin-IR in the dorsal horn. These results suggest that evoked pain is more tightly linked to SP than to galanin expression. If galanin's effects are inhibitory as the bulk of the literature suggests, its effects are subordinate to those of SP and to other changes following CCI.
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PMID:Galanin expression in neuropathic pain: friend or foe? 992 85

Increasing evidence supports an essential role for interleukin-6 (IL-6) in the development, differentiation, as well as de- and re-generation of neurons in the central nervous system (CNS). Both IL-6 and its specific receptor (IL-6R) are expressed on neurons and glial cells including astrocytes. In this study, we have analyzed the responses of primary rat astrocytes of various brain regions to IL-6 with respect to morphological changes and neurotrophin expression. Since IL-6 alone failed to initiate effects on astrocytes, we have examined whether the soluble IL-6R (sIL-6R) can modulate the responsiveness of to IL-6 in these cells. For this purpose, we used a highly active fusion protein of IL-6 and sIL-6R, which is designated Hyper-IL-6 (H-IL-6). We show that treatment of cultured astrocytes with Hyper-IL-6 promotes region-specific morphological changes of GFAP-positive astrocytes from typical stellate- to fibrous-like cells. In addition, we find that Hyper-IL-6 induces expression of neurotrophins (NTs) of the nerve growth factor (NGF)-family in a dose-dependent manner. Interestingly, astrocytes of various brain regions show differing patterns of cytokine-induced NT expression: NGF is maximally induced in cortex and hippocampus, NT-3 in hippocampus, and NT-4/5 in cortex and cerebellum. In summary, our results indicate that IL-6 in conjunction with sIL-6R regulates specific neurotrophin expression in astrocytes in a brain region dependent manner. Thus, the IL-6 system provides a local supply of neurotrophins that participate in diverse CNS functions such as protection of neurons from insults, neuronal survival, and neuro-immune responses.
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PMID:Role of interleukin-6 and soluble IL-6 receptor in region-specific induction of astrocytic differentiation and neurotrophin expression. 1034 Jul 60

Transection of the fimbria-fornix leads to retrograde degeneration of axotomized septal cholinergic neurons as manifested by loss of choline acetyltransferase and low-affinity nerve growth factor receptor (p75NGFR) immunoreactivity. Nerve growth factor administered into cerebral ventricles at the time of axotomy can prevent these changes, while ciliary neurotrophic factor can prevent the loss of p75NGFR immunostaining. Leukaemia inhibitory factor shares structural homologies with ciliary neurotrophic factor and has similar actions in the nervous system. Both proteins share the same signalling pathways, which involve the interleukin-6 transducing receptor components leukaemia inhibitory factor receptor beta and gp130. In this study, we compared the effects of leukaemia inhibitory factor, ciliary neurotrophic factor and nerve growth factor, administered into cerebral ventricles, on p75NGFR and choline acetyltransferase immunoreactivity in septal neurons after fimbria-fornix transection. We found that leukaemia inhibitory factor, like ciliary neurotrophic factor, prevents the loss of p75NGFR-stained medial septal neurons after fimbria-fornix axotomy, without maintaining choline acetyltransferase expression in these neurons. In addition, p75NGFR-immunostained neurons had significantly smaller mean diameter after axotomy in leukaemia inhibitory factor- and ciliary neurotrophic factor-treated animals as compared with either nerve growth factor-treated or unlesioned animals. These findings suggest that both leukaemia inhibitory factor and ciliary neurotrophic factor can prevent the axotomy-induced cell death of septal cholinergic neurons, but that, in contrast to nerve growth factor, these growth factors do not maintain the expression of choline acetyltransferase or the normal neuronal size of these injured neurons.
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PMID:Leukaemia inhibitory factor prevents loss of p75-nerve growth factor receptor immunoreactivity in medial septal neurons following fimbria-fornix lesions. 1036 99


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