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)

In order to investigate the role of neural regulation in corneal epithelial healing, we examined the effect of substance P (SP) on corneal epithelial migration using an organ culture system of rabbit corneas. We investigated the synergistic effects of SP with (1) growth factors: epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), and transforming growth factor-beta(TGF-beta); (2) extracellular matrix proteins: fibronectin, vitronectin, laminin, and collagen type IV; and (3) cytokines: interleukin-1alpha (IL-1alpha), IL-1beta, and interleukin-6 (IL-6). Rabbit corneal blocks were cultured in the absence or presence of various reagents for 24 hr. The corneal blocks were then fixed, dehydrated, embedded in paraffin and stained by hematoxylin-eosin, and the length of the path of epithelial migration was measured. The addition of SP alone, at concentrations up to 50 microg ml-1, did not affect epithelial migration. EGF, fibronectin, vitronectin, collagen type IV, and IL-6 stimulated epithelial migration, but bFGF, TGF-beta, laminin, IL-1alpha, and IL-1betadid not. The stimulatory effect of EGF on the epithelial migration was enhanced by the presence of SP. This synergistic effect of SP and EGF on corneal epithelial migration was abolished by the addition of an SP antagonist or enkephalinase. Other neurotransmitters (vasoactive intestinal peptide, calcitonin gene-related peptide, acetylcholine chloride, norepinephrine, serotonin) and tachykinins (neurokinin A, neurokinin B, kassinin, eledoisin, physalaemin) were examined, but none exhibited a synergistic effect with EGF. Interestingly, EGF alone stimulated the incorporation of 3H-thymidine into corneal epithelial cells, but the addition of SP with EGF did not enhance this effect. These results demonstrate that SP enhanced the EGF stimulation of corneal epithelial migration in vitro in a specific manner, suggesting a possible role of SP as a modulator of epithelial wound healing.
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PMID:Synergistic effect of substance P with epidermal growth factor on epithelial migration in rabbit cornea. 929 69

Interleukin-6 (IL-6) is a cytokine implicated as a key mediator of immune and inflammatory responses in psoriasis. Recent studies have shown that neuropeptides, substance P (SP) and vasoactive intestinal peptide (VIP), can modulate a production of IL-6 from cells, such as monocytes and astrocytes, participating in an immune reaction. The aim of this study was to assess the role of the neuropeptides on cytokine production of keratinocytes in physiologic or pathologic conditions. Cultured human keratinocytes derived from normal foreskin and psoriatic lesions were treated with various concentrations of SP or VIP, in the presence or absence of fetal bovine serum. The secretion of IL-6 by the treated keratinocytes was analyzed by enzyme-linked immunosorbent assay. Although neither SP nor VIP, by itself, was able to induce IL-6 synthesis in cultured human keratinocytes, we have found that SP, not VIP, significantly reduced 5% fetal bovine serum-induced IL-6 production in time- and dose-dependent fashion. This down-regulatory effect of SP was reversed by spantide, a SP antagonist. Lesional psoriatic keratinocytes showed a similar, but weaker, response when compared with normal keratinocytes. These data suggested that SP might modulate IL-6 synthesis of keratinocytes in either physiologic or pathologic conditions such as psoriasis.
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PMID:The effects of substance P and vasoactive intestinal peptide on interleukin-6 synthesis in cultured human keratinocytes. 1065 Dec 25

Interleukin-6 is a multifunctional cytokine that is found in high concentrations in intraocular fluids during the uveitic response. Although monocytic cells are a major source of interleukin-6, resident intraocular cells may also contribute to its accumulation in intraocular fluids during uveitis. The purpose of this study was to determine whether interleukin-6 is produced by pigmented ciliary epithelial cells and whether agents known to stimulate interleukin-6 production, such as interleukin-1beta, tumor necrosis factor-alpha, bacterial endotoxin, and stimulators of the adenylyl cyclase/adenosine 3',5'-cyclic monophosphate system, increase interleukin-6 production by these cells. Primary and first-passage cultures of nontransformed rabbit pigmented ciliary epithelial cells were incubated with the test agents for varying periods of time in serum-free medium and interleukin-6 levels in the cell-conditioned medium were measured by bioassay.Little, if any interleukin-6 was released from pigmented ciliary epithelial cells incubated for up to 18 hr in serum-free medium. Interleukin-1betastimulated interleukin-6 release in a time- and concentration-dependent manner. Tumor necrosis factor-alpha, although ineffective alone, increased interleukin-1beta-induced interleukin-6 release in a concentration-dependent manner when co-incubated with interleukin-1betafor 18 hr. However, tumor necrosis factor-alphadid not enhance interleukin-1beta-induced interleukin-6 release if co-incubated with interleukin-1betafor a shorter time (6 hr). A 6 hr exposure to bacterial endotoxin did not stimulate interleukin-6 release from pigmented ciliary epithelial cells. Co-incubation of pigmented ciliary epithelial cells with interleukin-1betaand agents that stimulate the adenyl cyclase/adenosine 3',5'-cyclic monophosphate system through cell surface G-protein transduced receptors, i.e. isoproterenol, vasoactive intestinal peptide or prostaglandin E(2), significantly enhanced the ability of interleukin-1betato stimulate interleukin-6 release. However, neither the adenyl cyclase activator, forskolin or the adenosine 3', 5'-cyclic monophosphate-mimetic, dibutyryl 3',5'-cyclic monophosphate enhanced interleukin-1beta-induced release of interleukin-6. These results indicate that the pigmented ciliary epithelium is one potential source of interleukin-6 and may contribute to the elevation in intraocular fluid interleukin-6 levels observed during various intraocular inflammatory episodes. Although agents that activate the adenyl cyclase/adenosine 3', 5'-cyclic monophosphate system through cell surface G-protein transduced receptors increased interleukin-1beta-induced release of interleukin-6, the ineffectiveness of forskolin and dibutryl 3', 5'-cyclic monophosphate suggest that simply increasing intracellular 3',5'-cyclic monophosphate is not sufficient to augment interleukin-1beta-induced release of interleukin-6. The significance of interleukin-6 in the intraocular inflammatory response is discussed in terms of its proposed role in an endogenous antiinflammatory system acting through induction of interleukin-1 receptor antagonist, soluble tumor necrosis factor receptor, acute-phase proteins and corticosteroids.
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PMID:Rabbit pigmented ciliary epithelium produces interleukin-6 in response to inflammatory cytokines. 1071 13

Astrocytes regulate clearance of glutamate from the vicinity of neurons. This helps to protect neurons directly from glutamate toxicity. Recent findings have indicated that a complex molecular interaction between neurons and astrocytes that is necessary for this protection occurs. In the present investigation the role of vasoactive intestinal peptide (VIP) in signaling between neurons and astrocytes was investigated. VIP was found to be necessary for the protective effects of astrocytes in a coculture system. VIP in combination with neuronal-conditioned medium enhanced glutamate uptake by astrocytes. Also, VIP enhanced the expression of the high-affinity VIP receptor, increased astrocytic release of interleukin-6, and indirectly reduced the toxicity of glutamate in neuronal-conditioned astrocyte medium. These results indicate that VIP is essential to the molecular interaction of neurons and astrocytes and is involved in the regulation of the protective effects of astrocytes for neurons.
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PMID:Neuronal release of vasoactive intestinal peptide is important to astrocytic protection of neurons from glutamate toxicity. 1083 3

Vasoactive intestinal peptide has been suggested to play some roles in inflammatory dermatoses such as atopic dermatitis and psoriasis. The aim of this study is to clarify the precise mechanisms of how vasoactive intestinal peptide is implicated in the pathogenesis of these disorders. We investigated the expression of vasoactive intestinal peptide and its receptors in normal human fibroblasts and keratinocytes, as well as in a human epidermal keratinocyte cell line DJM-1, using reverse transcription polymerase chain reaction and northern blotting. Type I VIP receptor mRNA was expressed in normal human keratinocytes and DJM-1 cells, and the latter also expressed type II receptor in lesser amounts. Neither type I nor type II VIP receptor mRNA was detected in fibroblasts, and vasoactive intestinal peptide transcript was not found in any cells examined. Type I VIP receptor mRNA was upregulated by Th1 cytokines (interferon-gamma), Th2 cytokines (interleukin-4), and tumor necrosis factor alpha, as well as vasoactive intestinal peptide itself, suggesting the presence of an autoregulatory loop. Vasoactive intestinal peptide increased cAMP production and cell proliferation of DJM-1 cells, and also induced the production of inflammatory cytokines such as interleukin-6, interleukin-8, and RANTES. The production of cAMP and cytokines was abrogated by a type I VIP receptor selective antagonist, indicating that type I receptor mediates these effects. Overall, these results suggest that upregulation of vasoactive intestinal peptide receptors by cytokines from inflammatory cells in the dermis enhances the proliferation and cytokine production of keratinocytes in response to vasoactive intestinal peptide from nerve endings. This cytokine network around keratinocytes may be involved in the pathogenesis of inflammatory dermatoses.
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PMID:Vasoactive intestinal peptide regulates its receptor expression and functions of human keratinocytes via type I vasoactive intestinal peptide receptors. 1134 64

The neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylyl cyclase-activating peptide (PACAP) are induced strongly in neurons after several types of injury, and exhibit neuroprotective actions in vitro and in vivo. It is thought that changes in expression of neuropeptides and other molecules in injured neurons are mediated by new factors produced in Schwann and immune cells at the injury site, a loss of target-derived factors, or a combination of mediators. To begin to determine the role of the inflammatory mediators, we investigated axotomy-induced changes in VIP and PACAP gene expression in the facial motor nucleus in severe combined immunodeficient (SCID) mice, and in mice with targeted mutations in specific cytokine genes. In normal mice, VIP and PACAP mRNA was induced strongly in facial motor neurons 4 days after axotomy. The increase in PACAP mRNA was blocked selectively in SCID mice, indicating that mechanisms responsible for VIP and PACAP gene induction are not identical. The loss of PACAP gene expression in SCID mice after axotomy was fully reversed by an infusion of normal splenocytes, suggesting that PACAP mRNA induction requires inflammatory mediators. PACAP and VIP mRNA inductions, however, were maintained in mice lacking leukemia inhibitory factor (LIF) and interleukin-6 (IL-6), and in mice lacking both receptors for tumor necrosis factor alpha (TNFalpha). The data suggest that an inflammatory response, most likely involving T lymphocytes, is necessary for the axotomy-induced increase in PACAP but not in VIP. LIF, IL-6, and TNFalpha, however, are not required for this response to injury.
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PMID:Lymphocyte regulation of neuropeptide gene expression after neuronal injury. 1451 53

Infections caused by Gram-negative bacteria constitute one of the major causes of septic shock, which results from the inability of the immune system to limit bacterial spread during the ongoing infection. In the last decade, it has been demonstrated that vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are two endogenous immunopeptides, which together with three G protein-coupled receptors (VPAC1, VPAC2, and PAC1) exert a significant, therapeutic effect attenuating the deleterious consequences of septic shock by balancing pro- and anti-inflammatory factors. We have recently shown PAC1 receptor involvement in vivo as an anti-inflammatory receptor, at least in part, by attenuating lipopolysaccharide-induced production of proinflammatory interleukin-6. The present study deepens in the protective role of PAC1 receptor in septic shock, elucidating its involvement in the modulation of neutrophil recruitment and in the expression of different molecular sensors such as intercellular adhesion molecule-1, vascular cell adhesion molecule-1, fibrinogen, serum amyloid A, and nitric oxide as important, systemic players of the development of septic shock. Our results, using a mice deficient in PAC1 and a PAC1 antagonist, show that VIP and PACAP as well as the PAC1 receptor are involved in neutrophil recruitment in different target organs, in adhesion molecules expression, and in coagulation-related molecule fibrinogen synthesis. Thus, this study provides some important insights with respect to the involvement of PAC1 into the complexities of sepsis and represents an advantage for the design of more specific drugs complementing standard intensive care therapy in severe sepsis, confirming VIP and PACAP as candidates for multitarget therapy of septic shock.
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PMID:Analysis of the role of the PAC1 receptor in neutrophil recruitment, acute-phase response, and nitric oxide production in septic shock. 1566 28

Cardiac ischemia-reperfusion alters sympathetic neurotransmission in the heart, but little is known about its effect on neuropeptide expression in sympathetic neurons. Ischemia followed by reperfusion induces the production of inflammatory cytokines in the heart, including interleukin-6 and cardiotrophin-1. These cytokines and related molecules inhibit the expression of neuropeptide Y (NPY), and stimulate the expression of vasoactive intestinal peptide (VIP), substance P (SubP), and galanin (GAL) in cultured sympathetic neurons. Therefore, we quantified NPY, VIP, SubP, and GAL mRNA in neurons of the stellate ganglia 1 week after ischemia-reperfusion to determine if neuropeptide expression was altered in cardiac sympathetic neurons. NPY, VIP, and SubP mRNAs were unchanged compared to unoperated control animals, but GAL mRNA was increased significantly. The increased GAL mRNA was not accompanied by elevated GAL peptide content in the stellate ganglia. Galanin content was increased significantly in the heart, however, indicating that elevated GAL mRNA led to increased peptide production. GAL content was increased in the left ventricle below the coronary artery ligation, but was not increased significantly in the atria or the base of the heart above the ligation. The buildup of GAL specifically in the damaged left ventricle is consistent with previous reports that GAL is transported to regenerating nerve endings after axon damage.
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PMID:Myocardial infarction stimulates galanin expression in cardiac sympathetic neurons. 1575 42

The objectives of this work were to observe the multiple immuno-regulating effects of vasoactive intestinal peptide (VIP) on synovial cells of collagen induced arthritis (CIA) rats and to determine whether the transcriptional factor-kappaB (NF-kappaB) signal pathway was involved. CIA was induced using female Wistar rats by native bovine type II collagen (C II) emulsified with complete Freund's adjuvant (CFA). Synovial cells from the knees of the CIA rats were cultivated, and the effects of VIP and VIP receptor inhibitor ([D-P-Cl-Phe(6),Leu(17)]-VIP, I) on proliferation and apoptosis of the synovial cells were assayed by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carcoxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS), flow cytometry, and DNA integrity. The effects of VIP and [D-P-Cl-Phe(6), Leu(17)]-VIP on mRNA expression of several cytokines in the synovial cells including tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), regulated upon activation, normal T-cell expressed and secreted (RANTES), inducible NO synthase (iNOS), matrix metalloproteinase-2 (MMP-2) and MMP-9 were estimated by quantitative reverse transcription-polymerase chain reaction (RT-PCR). Effects of VIP and [D-P-Cl-Phe(6), Leu(17)]-VIP on NF-kappaB activity were analyzed using luciferase gene reporter assays. Effects of VIP and [D-P-Cl-Phe(6),Leu(17)]-VIP on p65NF-kappaB expression of the synovial cells were examined by Western blot. Seventy-five percent of the induced rats developed CIA. VIP has multiple effects on synovial cells of CIA rats including decreasing proliferation, inducing apoptosis, and down-regulating mRNA expression of several inflammatory factors. VIP was found to play immuno-regulating roles through the down-regulation of the activity and expression of NF-kappaB, whereas VIP receptor blockade was found to counteract all the effects. In conclusion, VIP was found to ameliorate synovial cell functions of CIA rats through binding with receptors and further down-regulating NF-kappaB signal pathway, suggesting VIP is a potential anti-inflammatory and anti-rheumatic agent of CIA by blocking NF-kappaB.
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PMID:Vasoactive intestinal peptide ameliorates synovial cell functions of collagen-induced arthritis rats by down-regulating NF-kappaB activity. 1592 Nov 57

Interleukin-6 (IL-6), and the related cytokines IL-11, leukemia inhibitory factor (LIF) and oncostatin M (OSM), are potent stimulators of osteoclastic bone resorption. In the present study, we have addressed the possibility that the neuropeptide vasoactive intestinal peptide (VIP) may regulate the production of and/or sensitivity to the IL-6 family of cytokines in mouse calvarial osteoblasts. VIP stimulated IL-6 mRNA expression and protein release in a time- and concentration-dependent manner, whereas mRNA expression of the IL-6 receptor, as well as mRNA expressions of IL-11, LIF, OSM and their cognate receptors, were unaffected by VIP. In cells transfected with the IL-6 promoter coupled to luciferase, VIP increased transcriptional activity. The effects of VIP were shared by the related neuropeptide PACAP-38, belonging to the same superfamily of neuropeptides, whereas secretin did not have any effect, indicating that the effects were mediated by VPAC2 receptors. The effects of VIP were potentiated by the cyclic AMP phosphodiesterase inhibitor rolipram and mimicked by forskolin, indicating the involvement of the cyclic AMP/protein kinase A pathway. This was further demonstrated by the facts that the stimulatory effect of VIP on luciferase activity could be reversed by the PKA inhibitors H-89 and KT5720 and was mimicked by cyclic AMP analogues selective for PKA, but not by those selective for Epac. In addition, VIP enhanced the phosphorylation of CREB, as assessed by both immunocytochemical analysis and Western blot. The DNA binding activity of nuclear extracts to C/EBP was increased by VIP, whereas binding to AP-1 was decreased. In contrast, DNA binding to NF-kappaB, as well as nuclear translocation of NF-kappaB and C/EBP, were unaffected by VIP. The mRNA expressions of C/EBPbeta, C/EBPdelta, C/EBPgamma, c-Jun, JunB, c-Fos, Fra-1 and IkappaBalpha and protein level of IkappaBalpha were all unaffected by VIP. These observations, together, demonstrate that VIP stimulates IL-6 production in osteoblasts by a mechanism likely to be mediated by VPAC2 receptors and dependent on cyclic AMP/protein kinase A/CREB activation and also involving the transcription factors C/EBP and AP-1.
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PMID:Increased expression of interleukin-6 by vasoactive intestinal peptide is associated with regulation of CREB, AP-1 and C/EBP, but not NF-kappaB, in mouse calvarial osteoblasts. 1608 72

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