Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10145 (IL-8)
 23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The decidualized endometrium plays a role in regulating trophoblast invasion for successful implantation and maintenance of pregnancy. IL-1 beta, a proinflammatory cytokine, has been suggested to play a role in this process. Recently, several lines of evidence indicate the importance of p38 MAPK in various inflammatory responses. We investigated whether endometrial stromal cells (ESC) change their inflammatory responses to IL-1 beta as related to p38 MAPK phosphorylation during the process of decidualization. ESC were decidualized by the treatment with progesterone for 9 d, as determined as such by an increase in the production of prolactin and cAMP by the cells. Whereas IL-1 beta increased the production of IL-6, IL-8, and monocyte chemotactic protein-1, and expression of cyclooxygenase-2 mRNA in ESC cultured without treatment, the stimulatory effects of IL-1 beta were reduced in the decidualized cells. Treatment with SB202190, a p38 MAPK inhibitor, also reduced the stimulatory effects of IL-1 beta in nondecidualized ESC. P38 MAPK phosphorylation was increased by IL-1 beta in nondecidualized ESC, whereas the IL-1 beta-induced increase was suppressed in the decidualized cells. Treatment with 8-bromo-cAMP reduced IL-1 beta-induced phosphorylation of p38 MAPK in nondecidualized ESC. In contrast, treatment with H89, a protein kinase A inhibitor, reversed a reduction in IL-1 beta-induced p38 MAPK phosphorylation in the decidualized cells. In summary, decidualization seems to be a process during which endometrial cells diminish their response to IL-1 beta, a known key factor for implantation, leading to the down-regulation of inflammation-like events, which may be relevant to controlled trophoblast invasion. The altered property of decidualized cells is thought to be caused by attenuation of IL-1 beta-induced p38 MAPK phosphorylation in a way that involves the activation of the cAMP/protein kinase A pathway.
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PMID:Endometrial stromal cells undergoing decidualization down-regulate their properties to produce proinflammatory cytokines in response to interleukin-1 beta via reduced p38 mitogen-activated protein kinase phosphorylation. 1272 80

This report describes an unbiased method for systematically determining gene function in mammalian cells. A total of 20,704 predicted human full-length cDNAs were tested for induction of the IL-8 promoter. A number of genes, including those for cytokines, receptors, adapters, kinases, and transcription factors, were identified that induced the IL-8 promoter through known regulatory sites. Proteins that acted through a cooperative interaction between an AP-1 and an unrecognized cAMP response element (CRE)-like site were also identified. A protein, termed transducer of regulated cAMP response element-binding protein (CREB) (TORC1), was identified that activated expression through the variant CRE and consensus CRE sites. TORC1 potently induced known CREB1 target genes, bound CREB1, and activated expression through a potent transcription activation domain. A functional Drosophila TORC gene was also identified. Thus, TORCs represent a family of highly conserved CREB coactivators that may control the potency and specificity of CRE-mediated responses.
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PMID:Identification of a family of cAMP response element-binding protein coactivators by genome-scale functional analysis in mammalian cells. 1450 90

Human interleukin 8 (hIL-8), a neutrophil-activating and chemotactic cytokine, is known to play an important role in the pathogenesis of a large number of neutrophil-driven inflammatory diseases. This cytokine belongs to the family of CXC chemokines, mediating the response through binding to the seven-transmembrane helical G protein-coupled receptors CXCR1 and CXCR2. For the first time, we employed the expressed protein ligation (EPL) strategy to chemokine synthesis and subsequent modification. The ligation site was chosen with respect to the position of four cysteine residues within the hIL-8 sequence. Ligation with synthetic peptides that carry cysteine at their N-termini resulted in full-length hIL-8 and the specifically carboxyfluorescein-labelled analogue [K69(CF)]hIL-8(1-77). [K69(CF)]hIL-8(1-77) was fully active as shown by inhibition of cAMP production. Furthermore, this analogue was used to study receptor internalisation in human promyelotic HL60 cells that express CXCR1 and CXCR2 receptors. Binding and quenching studies were performed on HL60 membranes and suggest that the C-terminus of IL-8 is accessible to solvent in the receptor-bound state. Thus, we introduce here a powerful approach that allows the site-specific incorporation of chemical modifications into the sequence of chemokines, which opens new avenues for studying IL-8 function.
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PMID:Semisynthesis and application of carboxyfluorescein-labelled biologically active human interleukin-8. 1471 5

The production of antimicrobial peptides and proteins is essential for defense against infection. Many of the known human antimicrobial peptides are multifunctional, with stimulatory activities such as chemotaxis while simultaneously acting as natural antibiotics. In humans, eccrine appendages express DCD and CAMP, genes encoding proteins processed into the antimicrobial peptides dermcidin and LL-37. In this study we show that after secretion onto the skin surface, the CAMP gene product is processed by a serine protease-dependent mechanism into multiple novel antimicrobial peptides distinct from the cathelicidin LL-37. These peptides show enhanced antimicrobial action, acquiring the ability to kill skin pathogens such as Staphylococcus aureus and Candida albicans. Furthermore, although LL-37 may influence the host inflammatory response by stimulating IL-8 release from keratinocytes, this activity is lost in subsequently processed peptides. Thus, a single gene product encoding an important defense molecule alters structure and function in the topical environment to shift the balance of activity toward direct inhibition of microbial colonization.
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PMID:Postsecretory processing generates multiple cathelicidins for enhanced topical antimicrobial defense. 1497 12

The presence and the different functional aspects of cytokine-related molecules in invertebrates are described. Cytokine-like factors affect immune functions, such as cell motility, chemotaxis, phagocytosis and cytotoxicity. In particular, cell migration shows a species-specific effect for IL-1alpha and TNF-alpha and a dose-correlated effect for IL-8, PDGF-AB and TGF-beta1. Apart from some exceptions, the phagocytic effect increases significantly at all the concentrations tested and with all the species used. PDGF-AB, TGF-beta1 and IL-8 provoke conformational changes in mollusk immunocytes, involving the signaling transduction pathways of phosphatidylinositol and cAMP. PDGF-AB and TGF-beta1 partially inhibit the induced programmed cell death in an insect cell line, and the survival effect is mediated by the activation of phosphatidylinositol 3-kinase, PKA and PKC. The exogenous administration of these growth factors in an invertebrate wound repair model showed that they are able to control the wound environment and promote the repair process by accelerating the coordinated activities involved. Moreover, IL-1alpha, IL-2 and TNF-alpha are able to induce nitric oxide synthase. PDGF-AB and TGF-beta1 provoke an increase in neutral endopeptidase-24.11 (NEP)-like activity in membrane preparations from mollusk immunocytes, while NEP deactivates the PDGF-AB- and TGF-beta1-induced cell shape changes. Cytokines are also involved in invertebrate stress response in a manner extremely similar to that in vertebrates. Several studies suggest the existence on the mollusk immunocyte membrane of an ancestral receptor capable of binding both IL-2 and CRH. Furthermore, the competition found between CRH and a large number of cytokines supports the idea that invertebrate cytokine receptors show a certain degree of promiscuity. The multiple functions of cytokines detected in invertebrates underline another characteristic of mammalian cytokines, i.e. their great pleiotropicity. Altogether, the studies on the function of the invertebrate humoral factors show a close overlapping with those found in vertebrates, and the hypothesized missing correlation between invertebrate and vertebrate cytokine genes that is emerging from the limited molecular biology data present in literature might represent a very peculiar strategy followed by Nature in the evolution of cytokines.
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PMID:Invertebrate humoral factors: cytokines as mediators of cell survival. 1497 62

The neurotransmitter 5-hydroxytryptamine (5-HT), commonly known as serotonin, is stored at peripheral sites in mast cells and released from this peripheral source upon IgE cross-linking. In this study, we investigated the expression of serotoninergic receptors (5-HTR), the signaling pathway, and biological activity of 5-HT on human dendritic cells (DC), showing that immature and mature DC expressed mRNA for different serotoninergic receptors. Thereby, the mRNA of 5-HTR(1B), 5-HTR(1E), 5-HTR(2A), 5-HTR(2B), one splicing variant of the 5-HTR(3), 5-HTR(4), and 5-HTR(7) receptors were detected. Immature DC preferentially expressed mRNA for the heptahelical 5-HTR(1B), 5-HTR(1E), and 5-HTR(2B) receptors, while mature DC mostly expressed 5-HTR(4) and 5-HTR(7). The mRNA expression level of the ligand-gated cation channel 5-HTR(3) and the heptahelical 5-HTR(2A) did not significantly change during maturation. Isotype-selective receptor agonists allowed us to show that 5-HT stimulated 5-HTR(3)-dependent Ca(2+) influx in immature and mature DC. Moreover, we revealed that 5-HTR(1) and 5-HTR(2) receptor stimulation induced intracellular Ca(2+) mobilization via G(i/o) proteins in immature, but not mature, DC. Activation of 5-HTR(4) and 5-HTR(7) induced cAMP elevation in mature DC. Functional studies indicated that activation of 5-HTR(4) and 5-HTR(7) enhanced the release of the cytokines IL-1beta and IL-8, while reducing the secretion of IL-12 and TNF-alpha in mature DC. In summary, our study shows that 5-HT stimulated, in a maturation-dependent manner, different signaling pathways in DC. These data point to a role for 5-HT in regulating the immune response at peripheral sites.
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PMID:The serotoninergic receptors of human dendritic cells: identification and coupling to cytokine release. 1512 84

Pain is one of the hallmarks of inflammation. Opioid receptors mediate antipain responses in both the peripheral nervous system and CNS. In the present study, pretreatment of CCR1: mu-opioid receptor/HEK293 cells with CCL3 (MIP-1alpha) induced internalization of mu-opioid receptors and severely impaired the mu-opioid receptor-mediated inhibition of cAMP accumulation. Immunohistochemical staining showed that CCR1 and mu-opioid receptors were coexpressed on small to medium diameter neurons in rat dorsal root ganglion. Analysis of ligand-induced calcium flux showed that both types of receptors were functional. Pretreatment of neurons with CCL3 exhibited an impaired [D-Ala(2),N-MePhe(4),Gly-o15]enkephalin-elicited calcium response, indicative of the heterologous desensitization of mu-opioid receptors. Other chemokines, such as CCL2, CCL5, and CXCL8, exhibited similar inhibitory effects. Our data indicate that proinflammatory chemokines are capable of desensitizing mu-opioid receptors on peripheral sensory neurons, providing a novel potential mechanism for peripheral inflammation-induced hyperalgesia.
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PMID:Proinflammatory chemokines, such as C-C chemokine ligand 3, desensitize mu-opioid receptors on dorsal root ganglia neurons. 1521 Aug 21

Mucociliary clearance is a critical host defense that protects the lung. The mechanisms by which mucociliary function is altered by inflammation are poorly defined. Chronic exposure to cigarette smoke decreases ciliary beating and interferes with proper airway clearance. Bronchoalveolar lavage (BAL) fluid from smokers and ex-smokers has increased amounts of IL-8, which has played a critical role in airway inflammation. We hypothesized that IL-8 might interfere with stimulated ciliary beating in airway epithelium. To test this hypothesis, we stimulated bovine ciliated bronchial epithelial cells (BBECs) with a known activator of ciliary beat frequency (CBF), isoproterenol (ISO; 100 microM), in the presence or absence of IL-8 (100 pg/mL). We measured CBF digitally using the Sisson-Ammons Video Analysis (SAVA) system. CBF increased in untreated cells exposed to ISO (approximately 3 Hz) over baseline. In contrast, cells pre-incubated with IL-8 failed to respond to ISO. Pretreatment with IL-8 also blocked ISO-stimulated cAMP-dependent kinase (PKA) activation, which is known to control ISO-stimulated CBF. In addition, IL-8 pretreated cells revealed a marked decrease in PKA activity when cells were stimulated with forskolin (FSK; 10 microM). Cells were assayed specifically for cAMP-phosphodiesterase (PDE) activity. ISO-stimulated cells demonstrated an increase in PDE activity as compared to control. Pretreatment with IL-8 had no effect on ISO-stimulated PDE activity. Collectively, these data suggest that IL-8 appears to mediate its effect at the level of adenylyl cyclase. It is also possible that IL-8 may not only act as a chemotactic agent, but also as a potential autocrine/paracrine inhibitor of PKA-mediated stimulation of ciliary motility. In conclusion, IL-8 inhibits beta-agonist dependent ciliostimulation and such inhibition of stimulated ciliary activity may contribute to the impaired mucociliary clearance seen in airway diseases. Furthermore, since IL-8 levels are increased in the airway of cigarette smokers, it is likely they may be more resistant to the cilio and muco-ciliostimulating effects of beta-agonists.
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PMID:IL-8 inhibits isoproterenol-stimulated ciliary beat frequency in bovine bronchial epithelial cells. 1529 60

Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide mainly present in sensory nerve fibers, which is present in almost all organs, but it is also found in cultured rat type II alveolar epithelial cells (AEII). Our data have previously shown that CGRP may play an important role in inflammation as an immunomodulator. Proinflammatory factor IL-1beta induces CGRP release from neuron-derived sources. However, whether IL-1beta can induce CGRP secretion from a nonneural source, AEII cells, is not known. In the present study, we demonstrated that human AEII A549 cells expressed beta-CGRP, and IL-1beta (0.001-50 ng/ml) directly increased CGRP secretion from these cells in a time- and concentration-dependent manner. The mRNA level of beta-CGRP was also elevated by IL-1beta (1 ng/ml). In addition, we found that IL-1beta-induced CGRP production was mediated through the PKC-p38 mitogen-activated protein (MAP) kinase-NF-kappaB signaling pathway. Furthermore, IL-1beta-induced chemokines MCP-1 and IL-8 were partially inhibited by exogenous hCGRP (0.1-10 nM) and potentiated by hCGRP8-37 (0.1-10 nM), a CGRP1-receptor antagonist. In addition, the CGRP-inhibited chemokine effect was partially reduced by Rp-cAMP, a cAMP-PK inhibitor. These results suggest that AEII-derived CGRP may act in an autocrine/paracrine mode and play an important inhibitory role in the local area in lung inflammatory diseases.
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PMID:Interleukin-1beta induces beta-calcitonin gene-related peptide secretion in human type II alveolar epithelial cells. 1531 67

Glycoprotein hormone receptors (GPHRs) differ from the other seven transmembrane receptors mainly through a complex activation mechanism that requires the binding of a large hormone toward a large N-terminal ectodomain. The intramolecular mechanism of the signal transduction to the serpentine domain upon hormone binding at the ectodomain is not understood. To identify determinants at the GPHR ectodomain that may be involved in signal transduction, we first searched for homologous structural features. Based on high sequence similarity to the determined structures of the Nogo-receptor ectodomain and the intermolecular complex of the Interleukin-8 ligand (IL8) and the N-terminal peptide of the IL8 receptor (IL8RA), the hypothesis was developed that portions of the intramolecular components, Cysteine-box-2 and Cysteine-box-3, of the GPHR ectodomain interact and localize at the interface between ectodomain and serpentine domain. Indeed, point mutations within the D403EFN406 motif at Cysteine-box-3 of the thyrotropin receptor resulted in increased basal cAMP levels, suggesting that this motif may be important for transduction of the signal from the ectodomain to the transmembrane domain. New indications are provided about the tight spatial cooperation and relative location of the new epitope and other determinants at the thyrotropin receptor ectodomain, such as the leucine-rich repeat motif Ser281 and the cysteine boxes. According to the high sequence conservation, the results are of general relevance for the signal transduction mechanism of other glycoprotein hormone receptors such as choriogonadotrophic/luteinizing hormone receptor and follicle-stimulating hormone receptor.
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PMID:Identification of a novel epitope in the thyroid-stimulating hormone receptor ectodomain acting as intramolecular signaling interface. 1534 20


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