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)

Cytokine signaling involves the participation of many adaptor proteins, including the docking protein TNF receptor-associated factor-2 (TRAF-2), which is believed to transmit the TNF-alpha signal through both the I kappa B/NF-kappa B and c-Jun N-terminal kinase (JNK)/stress-related protein kinase (SAPK) pathways. The physiological role of TRAF proteins in cytokine signaling in intestinal epithelial cells (IEC) is unknown. We characterized the effect of a dominant-negative TRAF-2 delivered by an adenoviral vector (Ad5dnTRAF-2) on the cytokine signaling cascade in several IEC and also investigated whether inhibiting the TRAF-2-transmitting signal blocked TNF-alpha-induced NF-kappa B and IL-8 gene expression. A high efficacy and level of Ad5dnTRAF-2 gene transfer were obtained in IEC using a multiplicity of infection of 50. Ad5dnTRAF-2 expression prevented TNF-alpha-induced, but not IL-1 beta-induced, I kappa B alpha degradation and NF-kappa B activation in NIH-3T3 and IEC-6 cells. TNF-alpha-induced JNK activation was also inhibited in Ad5dnTRAF-2-infected HT-29 cells. Induction of IL-8 gene expression by TNF-alpha was partially inhibited in Ad5dnTRAF-2-transfected HT-29, but not in control Ad5LacZ-infected, cells. Surprisingly, IL-1 beta-mediated IL-8 gene expression was also inhibited in HT-29 cells as measured by Northern blot and ELISA. We concluded that TRAF-2 is partially involved in TNF-alpha-mediated signaling through I kappa B/NF-kappa B in IEC. In addition, our data suggest that TRAF-2 is involved in IL-1 beta signaling in HT-29 cells. Manipulation of cytokine signaling pathways represents a new approach for inhibiting proinflammatory gene expression in IEC.
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PMID:TNF receptor-associated factor-2 is involved in both IL-1 beta and TNF-alpha signaling cascades leading to NF-kappa B activation and IL-8 expression in human intestinal epithelial cells. 1020 81

1. The objective of the present paper was to evaluate the relevance of neuronal balance of cyclic AMP and cyclic GMP concentration for functional regulation of nociceptor sensitivity during inflammation. 2. Injection of PGE2 (10-100 ng paw-1) evoked a dose-dependent hyperalgesic effect which was mediated via a cyclic AMP-activated protein kinase (PKA) inasmuch as hyperalgesia was blocked by the PKA inhibitor H89. 3. The PDE4 inhibitor rolipram and RP73401, but not PDE3 and PDE5 inhibitors potentiated the hyperalgesic effects of PGE2. The hyperalgesic effect of dopamine was also enhanced by rolipram. Moreover, rolipram significantly potentiated hyperalgesia induced by carrageenan, bradykinin, TNF alpha, IL-1 beta, IL-6 and IL-8. This suggests that neuronal cyclic AMP mediates the prostanoid and sympathetic components of mechanical hyperalgesia. Moreover, in the neuron cyclic AMP is mainly metabolized by PDE4. 4. To examine the role of the NO/cyclic GMP pathway in modulating mechanical hyperalgesia, we tested the effects of the soluble guanylate cyclase inhibitor, ODQ. This substance counteracts the inhibitory effects of the NO donor, SNAP, on the hyperalgesia induced by PGE2. 5. The ODQ potentiated hyperalgesia induced by carrageenan, bradykinin, TNF alpha, IL-1 beta, IL-6 and IL-8. In contrast, ODQ had no significant effect on the hyperalgesia induced by PGE2 and dopamine. This indicates that the hyperalgesic cytokines may activate soluble guanylate cyclase, which down-regulate the ability of these substances to cause hyperalgesia. This event appears not to be mediated by prostaglandin or dopamine. 6. In conclusion, the results presented in this paper confirm an association between (i) hyperalgesia and elevated levels of cyclic AMP as well as (ii) antinociception and elevated levels of cyclic GMP. The intracellular levels of cyclic AMP that enhance hyperalgesia are controlled by the PDE4 isoform and appear to result in activation of protein kinase A whereas the intracellular levels of cyclic GMP results from activation of a soluble guanylate cyclase.
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PMID:Pharmacological modulation of secondary mediator systems--cyclic AMP and cyclic GMP--on inflammatory hyperalgesia. 1040 57

We have previously demonstrated that endothelin-1 (Et-1) induces human central nervous system-derived endothelial cells (CNS-EC) to produce and secrete the chemokine interleukin 8 (IL-8). In the present study, we use specific inhibitors and activators to elucidate the signal transduction pathways involved in this process. Et-1-induced IL-8 production was blocked by ET(A) receptor antagonist BQ610, but not by ET(B) receptor antagonist BQ788, demonstrating that CNS-EC activation is initiated by Et-1 binding to the ET(A) receptor. IL-8 mRNA expression is blocked by the protein kinase C inhibitor bisindolylmaleimide or protein tyrosine kinase inhibitors, genestein and geldanamycin, establishing the involvement of the protein kinase C and protein tyrosine kinase pathways in the activation process. The transcription factor, NF-kappaB, is involved in Et-1 activation as determined by specific inhibitors of translocation and direct analysis of DNA-binding proteins. Neither inhibition nor activation of cAMP-dependent protein kinase affected IL-8 production in the absence or presence of Et-1. Similarly, no effect was observed upon inhibition of protein phosphatases by okadaic acid. Thus, the signal transduction process induced by Et-1 in CNS-EC, leading to increased mRNA IL-8 expression, is initiated by Et-1 binding to ET(A) receptor followed by subsequent activation of protein kinase C, protein tyrosine kinase, and NF-kappaB. Because increased expression of Et-1 is associated with hypertension and stroke and IL-8 is likely to be involved in the accumulation of neutrophils causing tissue damage in ischemic/reperfusion injury, identification of the mechanism involved in the Et-1-induced increase in IL-8 production may have significant therapeutic value.
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PMID:Endothelin-1-induced interleukin-8 production in human brain-derived endothelial cells is mediated by the protein kinase C and protein tyrosine kinase pathways. 1043 17

Stabilization of mRNAs contributes to the strong and rapid induction of genes in the inflammatory response. The signaling mechanisms involved were investigated using a tetracycline-controlled expression system to determine the half-lives of interleukin (IL)-6 and IL-8 mRNAs. Transcript stability was low in untreated HeLa cells, but increased in cells expressing a constitutively active form of the MAP kinase kinase kinase MEKK1. Destabilization and signal-induced stabilization was transferred to the stable beta-globin mRNA by a 161-nucleotide fragment of IL-8 mRNA which contains an AU-rich region, as well as by defined AU-rich elements (AREs) of the c-fos and GM-CSF mRNAs. Of the different MEKK1-activated signaling pathways, no significant effects on mRNA degradation were observed for the SAPK/JNK, extracellular regulated kinase and NF-kappaB pathways. Selective activation of the p38 MAP kinase (=SAPK2) pathway by MAP kinase kinase 6 induced mRNA stabilization. A dominant-negative mutant of p38 MAP kinase interfered with MEKK1 and also IL-1-induced stabilization. Furthermore, an active form of the p38 MAP kinase-activated protein kinase (MAPKAP K2 or MK2) induced mRNA stabilization, whereas a negative interfering MK2 mutant interfered with MAP kinase kinase 6-induced stabilization. These findings indicate that the p38 MAP kinase pathway contributes to cytokine/stress-induced gene expression by stabilizing mRNAs through an MK2-dependent, ARE-targeted mechanism.
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PMID:The p38 MAP kinase pathway signals for cytokine-induced mRNA stabilization via MAP kinase-activated protein kinase 2 and an AU-rich region-targeted mechanism. 1048 49

Lipoxins (LX) are lipoxygenase-derived eicosanoids generated during inflammation. LX inhibit polymorphonuclear neutrophil (PMN) chemotaxis and adhesion and are putative braking signals for PMN-mediated tissue injury. In this study, we report that LXA4 promotes another important step in the resolution phase of inflammation, namely, phagocytosis of apoptotic PMN by monocyte-derived macrophages (Mphi). LXA4 triggered rapid, concentration-dependent uptake of apoptotic PMN. This bioactivity was shared by stable synthetic LXA4 analogues (picomolar concentrations) but not by other eicosanoids tested. LXA4-triggered phagocytosis did not provoke IL-8 or monocyte chemoattractant protein-1 release. LXA4-induced phagocytosis was attenuated by anti-CD36, alphavbeta3, and CD18 mAbs. LXA4-triggered PMN uptake was inhibited by pertussis toxin and by 8-bromo-cAMP and was mimicked by Rp-cAMP, a protein kinase A inhibitor. LXA4 attenuated PGE2-stimulated protein kinase A activation in Mphi. These results suggest that LXA4 is an endogenous stimulus for PMN clearance during inflammation and provide a novel rationale for using stable synthetic analogues as anti-inflammatory compounds in vivo.
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PMID:Cutting edge: lipoxins rapidly stimulate nonphlogistic phagocytosis of apoptotic neutrophils by monocyte-derived macrophages. 1065 8

Acute and chronic interstitial lung diseases are accompanied by evidence of inflammation and vascular injury. Thrombin activity in bronchoalveolar lavage fluid from such conditions is often increased, as well as interleukin (IL)-8. We observed that conditioned medium from lung fibroblasts exposed to thrombin has chemotactic activity for polymorphonuclear cells, and that this activity can be abolished by antibody to IL-8. We report that thrombin stimulates expression of IL-8 in human lung fibroblasts on both the messenger RNA and protein levels in a time- and dose-dependent manner. Stimulation of IL-8 expression by thrombin is inhibited by specific thrombin inhibitors. Synthetic thrombin receptor agonist peptide-14 mimics thrombin's stimulation of IL-8 expression in a dose-dependent manner consistent with the idea that upregulation of IL-8 by thrombin in human lung fibroblasts requires cleavage of proteolytically activated receptor-I. We demonstrate further that thrombin-induced IL-8 synthesis is regulated by protein kinase (PK) C. PKC-gamma may be involved in the upregulation of lung fibroblast IL-8 by thrombin because stimulation of lung fibroblasts with thrombin caused significant upregulation of PKC-gamma and because PKC-gamma antisense oligonucleotides inhibited the accumulation of PKC-gamma protein and IL-8 protein. Our data suggest that the PKC-gamma isoform increase observed after thrombin stimulation is required for thrombin-induced IL-8 formation by human lung fibroblasts.
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PMID:Thrombin upregulates interleukin-8 in lung fibroblasts via cleavage of proteolytically activated receptor-I and protein kinase C-gamma activation. 1065 45

Cytokines, the hallmarks of infectious and inflammatory diseases, modify phagocyte activities and thus may interfere with the immunomodulating properties of antibacterial agents. We have investigated whether various proinflammatory cytokines (interleukin 1 [IL-1], IL-6, IL-8, gamma interferon, tumor necrosis factor alpha [TNF-alpha], and granulocyte-macrophage colony-stimulating factor [GM-CSF]) modify two macrolide properties, i.e., inhibition of oxidant production by polymorphonuclear neutrophils (PMN) and cellular uptake. Roxithromycin and two ketolides, HMR 3647 and HMR 3004, were chosen as the test agents. TNF-alpha and GM-CSF (but not the other cytokines) decreased the inhibitory effect of HMR 3647 only on oxidant production by PMN. Fifty percent inhibitory concentrations were, however, in the same range in control and cytokine-treated cells (about 60 to 70 microgram/ml), suggesting that HMR 3647 acts downstream of the priming effect of cytokines. In contrast, the impairment of oxidant production by roxithromycin and HMR 3004 was unchanged (or increased) in cytokine-treated cells. This result suggests that HMR 3004 (the strongest inhibitory drug, likely owing to its quinoline side chain) and roxithromycin act on a cellular target upstream of cytokine action. In addition, TNF-alpha and GM-CSF significantly (albeit moderately) impaired (by about 20%) the uptake of the three molecules by PMN. The inhibitory effect of these two cytokines seems to be related to activation of the p38 mitogen-activated protein kinase. Our data also illuminate the mechanism underlying macrolide uptake: protein kinase A- and tyrosine kinase-dependent phosphorylation seems to be necessary for optimal uptake, while protein kinase C activation impairs it. The relevance of our data to the clinical setting requires further investigations, owing to the complexity of the cytokine cascade during infection and inflammation.
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PMID:Effect of proinflammatory cytokines on the interplay between roxithromycin, HMR 3647, or HMR 3004 and human polymorphonuclear neutrophils. 1068 11

We report the presence of interleukin (IL)-8-immunoreactive molecules in hemocytes from the mollusc Mytilus galloprovincialis. Functional studies demonstrate that recombinant human (rh)IL-8 provokes conformational changes, induces chemotaxis, and increases bacterial phagocytic activity in hemocytes. rhIL-8 induces cell shape changes via protein kinase A and C pathways. These morphological changes are followed by reorganization of the actin microfilaments. The findings suggest that, as previously reported for other cytokines, IL-8 is well conserved and deeply involved in immune functions from invertebrates to mammals.
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PMID:Immunomodulation by recombinant human interleukin-8 and its signal transduction pathways in invertebrate hemocytes. 1082 50

Downregulation of pro-inflammatory events in the immune response to Mycobacterium tuberculosis is critical to prevent host tissue injury. Interleukin (IL-)10 is an important anti-inflammatory cytokine secreted in human tuberculosis but little is known about the control of such IL-10 release. Using an established cellular model, we measured IL-10 secretion after phagocytosis of M. tuberculosis. Phagocytosis of M. tuberculosis but not of inert latex beads by human monocytic (THP-1) cells resulted in IL-10 secretion maximal at 24 h. The magnitude and kinetics of IL-10 secretion were distinct from IL-10 secretion after phagocytosis of yeast-derived zymosan and depended on transcriptional activity and protein synthesis in infected monocytes. IL-10 secretion was decreased in a dose-dependent manner by specific inhibitors of tyrosine kinases, protein kinase (PK) C and PKA. Inhibition of more than one pathway did not result in further synergistic or additive reduction in IL-10 secretion. Finally, specific neutralising antibody directed against IL-10 demonstrated that IL-10 secreted by infected monocytic cells did not block autologous IL-8 secretion.
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PMID:Regulation of IL-10 secretion after phagocytosis of Mycobacterium tuberculosis by human monocytic cells. 1085 63

We have previously reported that human airway smooth-muscle (ASM) cells produce abundant interleukin (IL)-8, a major neutrophil chemoattractant involved in asthma exacerbations. Here, we tested the effects of the beta(2)-agonists salbutamol (Salbu) and salmeterol (Salme) on IL-8 release and tumor necrosis factor (TNF)-alpha-induced IL-8 release from ASM cells. We found that TNF-alpha strongly enhanced IL-8 release in a time- and concentration-dependent manner, whereas Salbu, Salme, the direct adenylyl cyclase activator forskolin (FSK), and the cyclic monophosphate (cAMP) analogue 8-bromoadenosine 3',5'-cAMP (8-Br-cAMP) alone weakly stimulated IL-8 release. TNF-alpha (10 ng/ml)-induced IL-8 release was markedly inhibited by the steroids dexamethasone (Dex) (0.1 to 10 microM) and fluticasone (Flut) (0.01 to 1 microM) but unaffected by Salbu, Salme, FSK, or 8-Br-cAMP. However, a combination of Dex (1 microM) or Flut (0.1 microM) with Salbu (10 microM), Salme (1 microM), FSK (10 microM), or 8-Br-cAMP (10 and 100 microM) significantly enhanced the inhibition by Dex or Flut alone. Experiments with KT5720, a selective inhibitor of cAMP-dependent protein kinase A; rolipram, a selective inhibitor of type IV phosphodiesterase; and ICI-118,551, a beta(2)-receptor antagonist, suggested that the synergistic inhibition was mediated by beta(2)-receptor in a cAMP-dependent manner. This novel synergistic interaction of beta(2)-agonists and steroids may partly explain the benefits that result when these agents are combined to treat asthma.
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PMID:Synergistic inhibition by beta(2)-agonists and corticosteroids on tumor necrosis factor-alpha-induced interleukin-8 release from cultured human airway smooth-muscle cells. 1087 56


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