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)

We have monitored glial cell line-derived neurotrophic factor (GDNF) secretion from rat C6 glioblastoma cells by ELISA. Representative cytokines, neurotrophins, growth factors, neuropeptides, and pharmacological agents were tested for their ability to modulate GDNF release. Whereas most factors tested had minimal effect, a 24-h treatment with fibroblast growth factor-1, -2, or -9 elevated secreted GDNF protein levels five- to 10-fold. The proinflammatory cytokines interleukin-1beta, interleukin-6, tumor necrosis factor-alpha, and lipopolysaccharide elevated GDNF release 1.5- to twofold. Parallel studies aimed at elucidating intracellular events that may regulate GDNF synthesis/release demonstrated the involvement of multiple signaling pathways. GDNF levels were increased by phorbol 12,13-didecanoate (10 nM) activation of protein kinase C, the Ca2+ ionophore A23187 (1 microM), okadaic acid (10 nM) inhibition of type-2A protein phosphatases, nitric oxide donors (1 mM), and H2O2 (1 mM)-induced oxidative stress. Elevation of cyclic AMP levels by either forskolin (10 microM) or dibutyryl cyclic AMP (1 mM) repressed GDNF secretion, as did treatment with the glucocorticoid dexamethasone (1 microM). Our results demonstrate that diverse biological factors are capable of modulating GDNF protein levels and that multiple signal transduction systems can regulate GDNF synthesis and/or release.
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PMID:Regulation of glial cell line-derived neurotrophic factor release from rat C6 glioblastoma cells. 945 47

Numerous purified growth factors as well as yet-unidentified neurotrophic activities within mesencephalic glia support the survival of dopaminergic neurons. To further characterize the functional role of these multiple growth factor influences in dopaminergic cell development, various purified growth factors as well as mesencephalic glial-conditioned medium (CM) were screened for effects on dopaminergic cell survival and glial numbers in serum-free low density cultures of the dissociated embryonic day (E) 15 and E17 rat mesencephalon. In E15 mesencephalic cultures, dopaminergic cell survival increased with brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), basic fibroblast growth factor (bFGF), transforming growth factor alpha (TGFalpha), insulin-like growth factor-1 (IGF-1), platelet-derived growth factor-BB (PDGF-BB), and interleukin-6 (IL-6). bFGF, TGFalpha, PDGF, and IL-6 also stimulated glial proliferation as demonstrated by autoradiographic labeling for 3H-thymidine. Moreover, CM derived from the mesencephalic glial cell line Mes42 completely prevented the death of E15 dopaminergic neurons within the initial days of cultivation. In E17 mesencephalic cultures, survival-promoting effects on dopaminergic neurons were present with BDNF, GDNF, and bFGF. TGFalpha, IGF-1, PDGF-BB, and IL-6 stimulated glial proliferation but did not affect dopaminergic cell survival. Similarly, mesencephalic glial-CM completely failed to support the survival of E17 dopaminergic neurons. These observations demonstrate that during embryonic development, dopaminergic cell survival sequentially depends on distinct sets of growth factors. The concomitant loss of sensitivity of developing dopaminergic neurons for mesencephalic glial-CM as well as TGFalpha, IGF-1, PDGF-BB, and IL-6 further provides evidence that these growth factors indirectly affect early dopaminergic neurons through glial-mediated processes and suggests a crucial role of glia during the initial stages of neuronal development.
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PMID:Changing responsiveness of developing midbrain dopaminergic neurons for extracellular growth factors. 951 4

The undisturbed development of the enteric nervous system depends on the supply of various neurotrophic factors during ontogenesis. Besides glial cell line-derived neurotrophic factor (GDNF), leukemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF) take part in its development. CNTF and LIF belong to the interleukin-6 (IL-6) family of cytokines. The combination of IL-6 and the soluble IL-6 receptor accelerates peripheral nerve regeneration. In this study, we examined the effect of the fusion protein Hyper-IL-6, which consists of IL-6 and the soluble receptor sIL-6R, on neurite outgrowth and neuronal survival in vitro. Myenteric plexus of newborn rats was dissected and dissociated. Cells were grown in either serum-free chemically defined medium alone or medium supplemented with sIL-6R, IL-6, sIL-6+IL-6, Hyper-IL-6, CNTF, LIF, or GDNF. Average neurite outgrowth per neuron was highest in GDNF-treated and Hyper-IL-6-treated cultures. The number of neurite-bearing neurons was reduced in GDNF cultures compared with Hyper-IL-6-treated cells, so that the total neurite outgrowth was maximal after Hyper-IL-6 stimulation. Hyper-IL-6 furthermore stimulated neuronal survival and morphologic differentiation of the enteric glia.
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PMID:The IL-6/sIL-6R fusion protein hyper-IL-6 promotes neurite outgrowth and neuron survival in cultured enteric neurons. 1038 65

The mRNA levels of nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF), and interleukin-6 (IL-6) were examined in sural nerves of 22 patients with acute necrotizing vasculitic neuropathies. NGF, GDNF, and IL-6 mRNAs were upregulated and CNTF mRNA was downregulated in the lesioned nerves, but their up- and down-regulation levels were not correlated with each other, showing that these mRNAs were independently expressed. The expression of NGF and CNTF mRNAs was clearly correlated with the degree of infiltrated macrophages and T cells, and myelinated fiber density, respectively. These findings indicate that these neurotrophic factors are differentially expressed temporally and spatially in the vasculitic nerve lesion by an underlying pathology-related process.
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PMID:Pathology-related differential expression regulation of NGF, GDNF, CNTF, and IL-6 mRNAs in human vasculitic neuropathy. 1136 Feb 69

Although neurotrophic factors are defined as molecules that maintain neuronal cells, they possess a range of functions outside the nervous system. For example, glial cell line-derived neurotrophic factor is essential for ureteric branching in kidney morphogenesis and for regulating the fate of stem cells during spermatogenesis. Leukemia inhibitory factor, a member of the interleukin-6 (IL-6) ciliary neurotrophic factor family, inhibits differentiation of embryonic stem cells, induces tubulogenesis in the embryonic kidney, and regulates sperm differentiation. Other IL-6 family members are important in cardiac differentiation and they have pleiotropic functions in the hematopoietic and immune systems. Although neurotrophin receptors have been found on a number of non-neuronal tissues, they represent mostly truncated receptor isoforms that are incapable of signal transduction and may have scavenger or dominant negative functions. However, several examples can be presented of essential non-neuronal functions played by neurotrophins in e.g., cardiac, hair follicle, and vascular differentiation, and the maintenance of immune cells.
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PMID:The neurotrophic factors in non-neuronal tissues. 1152 99

In the peripheral nervous system regeneration and gradual functional restoration occur following peripheral nerve injury. Growth of regenerating axons depends on the presence of diffusible neurotrophic factors, in addition to the substratum. Neurotrophic factors that are involved in peripheral nerve regeneration include nerve growth factor, brain-derived neurotrophic factor, ciliary neurotrophic factor, glial cell line-derived neurotrophic factor, and interleukin-6. Recent functional and expression studies of basic fibroblast growth factor and its receptors have emphasized a physiological role of these molecules in the peripheral nervous system. Basic fibroblast growth factor and its receptors are constitutively expressed in dorsal root ganglia and the peripheral nerve. These molecules display an upregulation in dorsal root ganglia and in the proximal and distal nerve stumps following peripheral nerve injury. In the ganglia these molecules show a mainly neuronal expression, whereas at the lesion site of the nerve, Schwann cells and invading macrophages represent the main cellular sources of basic fibroblast growth factor and the receptors 1-3. Exogenously applied basic fibroblast growth factor mediates rescue effects on injured sensory neurons and supports neurite outgrowth of transectioned nerves. Regarding the expression patterm and the effects after exogenous administration of basic fibroblast growth factor, this molecule seems to play a physiological role during nerve regeneration. Thus, basic fibroblast growth factor could be a promising candidate to contribute to the development of new therapeutic strategies for the treatment of peripheral nerve injuries.
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PMID:The role of basic fibroblast growth factor in peripheral nerve regeneration. 1168 96

The mRNA levels of nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), and interleukin-6 (IL-6) were examined in sural nerves of 22 patients with chronic inflammatory demyelinating polyneuropathy (CIDP). The mRNAs for NGF, GDNF, LIF, and IL-6 were upregulated, whereas CNTF mRNA was downregulated significantly in the nerves. The NGF, GDNF, and CNTF, but not LIF mRNA expressions were parallel to those of the cognate receptors, suggesting that these cognate soluble receptors effectively present these factors to maintain and regenerate the axons. Furthermore, IL-6 mRNA expression was significantly parallel to both binding and signal-transducing receptor expression, implying a role of the IL-6 signal for non-neuronal cells in CIDP. These findings indicate that multiple neurotrophic growth factors and cytokines are expressed cooperatively with their concomitant receptors in the nerve lesions of CIDP and play an important role particularly in nerve repair.
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PMID:Parallel expression of neurotrophic factors and their receptors in chronic inflammatory demyelinating polyneuropathy. 1193 79

There are various neurotrophic factors, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) and interleukin-6 (IL-6), which are essential for the promotion of neuronal survival (prevention of apoptosis), differentiation and regeneration in the central nervous system. Neurotrophic factors, neurotrophic factor-like substances and inducers of neurotrophic factor biosynthesis have enormous therapeutic potential for serious neuronal diseases such as Alzheimer's disease or traumatic, chemical and ischemic lesions in the brain. The clarification of the mechanism in neurotrophic factor biosynthesis is important in understanding the development of the drugs that stimulate neurotrophic factor production. In this review, we describe these mechanisms in the biosynthesis of NGF, BDNF, GDNF and IL-6, and also discuss the drugs that could possibly promote neurotrophic factor biosynthesis. (c) 2002 Prous Science. All rights reserved.
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PMID:The Signaling Pathway of Neurotrophic Factor Biosynthesis. 1267 25

Microglial activation and inflammation are associated with progressive neuronal apoptosis in neurodegenerative human brain disorders. We sought to investigate molecular signaling mechanisms that govern activation of microglia in apoptotic neuronal degeneration. We report here that the active form of matrix metalloproteinase-3 (MMP-3) was released into the serum-deprived media (SDM) of PC12 cells and other media of apoptotic neuronal cells within 2-6 h of treatment of the cells, and SDM and catalytic domain of recombinant MMP-3 (cMMP-3) activated microglia in primary microglia cultures as well as BV2 cells, a mouse microglia cell line. Both SDM and cMMP-3 induced generation of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), IL-1beta, and interleukin-1 receptor antagonist but not IL-12 and inducible nitric oxide synthase, which are readily induced by lipopolysaccharide, in microglia, suggesting that there is a characteristic pattern of microglial cytokine induction by apoptotic neurons. Neither glial cell line-derived neurotrophic factor nor anti-inflammatory cytokines, such as IL-10 and transforming growth factor-beta1, were induced. SDM and cMMP-3 extensively released TNF-alpha from microglia and activated the nuclear factor-kappaB pathway, and these microglial responses were totally abolished by preincubation with an MMP-3 inhibitor, NNGH [N-isobutyl-N-(4-methoxyphenylsulfonyl)-glycylhydroxamic acid]. MMP-3-mediated microglial activation mostly depended on ERK (extracellular signal-regulated kinase) phosphorylation but not much on either JNK (c-Jun N-terminal protein kinase) or p38 activation. Conditioned medium of SDM- or cMMP-3-activated BV2 cells caused apoptosis of PC12 cells. These results strongly suggest that the distinctive signal of neuronal apoptosis is the release of active form of MMP-3 that activates microglia and subsequently exacerbates neuronal degeneration. Therefore, the release of MMP-3 from apoptotic neurons may play a major role in degenerative human brain disorders, such as Parkinson's disease.
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PMID:Matrix metalloproteinase-3: a novel signaling proteinase from apoptotic neuronal cells that activates microglia. 1581 1

A growing body of evidence suggests that diverse growth factors such as neurotrophins (NTs), insulin-like growth factor-1 (IGF-1), and glial cell line-derived neurotrophic factor (GDNF) can be released via the regulated secretory pathway in neuronal cells, possibly representing a mechanism for preferentially supplying these growth factors to active synapses. Here we investigated whether interleukin-6 (IL-6), a member of the family of neuropoietic cytokines, can be released via stimulus-coupled secretion as well. IL-6 was expressed in PC12 cells, a neuronal model cell line that is frequently used for the study of vesicle release and trafficking. Regulated secretion of this cytokine was induced by 0.5 mM ATP and treatment with epidermal growth factor (EGF) and nerve growth factor (NGF). Release induced by 0.5 mM ATP but not by NGF or EGF depended on the presence of extracellular Ca(++). Furthermore, IL-6 colocalized with the dense core vesicle (DCV)-marker secretogranin-II (Sg-II) in transfected PC12 cells. Our data suggest that the neuropoietic cytokine IL-6 can be sorted to the regulated secretory pathway in neuronal cells and indicate a potential role for this cytokine in synaptic plasticity.
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PMID:Release of interleukin-6 via the regulated secretory pathway in PC12 cells. 1650 78


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