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

Dietary omega-3 polyunsaturated fatty acids (omega-3 PUFA) reduce sunburn, an acute inflammatory response, in humans. We assessed whether this may be mediated by reduced ultraviolet-B (UV-B) induction of proinflammatory mediators tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 beta, IL-6, IL-8 and prostaglandin (PG)E(2) in healthy skin. In a double-blind, randomized study, 28 humans received 4 g daily of 95% ethyl esters of eicosapentaenoic acid (EPA) or oleic acid (OA) orally for 3 months. Skin biopsies and suction blister fluid were taken from unexposed and UV-B-exposed skin and examined for mediator expression immunohistochemically and quantitatively by immunoassay; plasma levels were also assayed. The subjects taking EPA, but not OA, showed a significant rise in their minimal erythemal dose (MED) (data reported elsewhere). Before supplementation, irradiation with 3x MED UV-B increased blister fluid TNF-alpha, IL-6, IL-8 and PGE(2) at 16 h (all P < 0.001). No significant change occurred in baseline or UV-B-induced skin levels of cytokines after either supplement, whereas UV-B induction of PGE(2) was abolished after EPA but not OA. Immunohistochemical expression of the cytokines at baseline and after UV-B was unaltered by EPA and OA; circulating cytokine and PGE(2) levels were also unchanged. Hence, in healthy skin in vivo, there was no evidence that reduction of the sunburn response by EPA is mediated by the proinflammatory cytokines examined; abrogation of UV-B-generated PGE(2) may play a role.
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PMID:Influence of eicosapentaenoic acid, an omega-3 fatty acid, on ultraviolet-B generation of prostaglandin-E2 and proinflammatory cytokines interleukin-1 beta, tumor necrosis factor-alpha, interleukin-6 and interleukin-8 in human skin in vivo. 1536 34

Staphylococcus aureus is the major cause of osteomyelitis or bone infection, leading to major morbidity, often in children. Little is known about immunopathogenesis of osteomyelitis, although uncontrolled inflammation is a major clinical feature. This study investigated effects of dexamethasone, PGE(2) and T(h)2 cytokines, all potential down-regulatory mediators, on control of S. aureus-induced C-X-C (CXCL8, CXCL10) and C-C (CCL5, CCL2) chemokine gene expression and secretion from human osteoblastic MG-63 cells and primary NHOst cells. Chemokine mRNA expression and secretion were reduced 50-75% by dexamethasone, whereas PGE(2) doubled mRNA accumulation, as detected by RNase protection assay and RT-PCR, but decreased chemokine secretion 33-71% (P < 0.05). IL-10 reduced chemokine mRNA accumulation by 20-40% in MG-63 cells. IL-4 and -13 decreased CXCL8 but not CXCL10 gene expression. IL-10 and IL-13 reduced S. aureus-induced osteoblast C-X-C chemokine secretion, whereas IL-4 decreased CXCL8 secretion 2.5-fold and increased CXCL10 secretion 3-fold (all P < 0.05). In contrast, T(h)2 cytokines increased C-C chemokine secretion from MG-63 osteoblastic cells (P < 0.05), and IL-4 and IL-13 caused similar up-regulation of CCL2 secretion from primary osteoblasts. In summary, during S. aureus infection of osteoblasts, T(h)2 cytokines, dexamethasone and PGE(2) have diverse, sometime upregulatory actions on C-C and C-X-C chemokines due to both pre- and post-transcriptional effects on chemokine secretion.
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PMID:Regulation of chemokine gene expression and secretion in Staphylococcus aureus-infected osteoblasts. 1537 6

An active role for C-reactive protein (CRP) in inflammatory vascular diseases has been recently suggested. Monocytes play an important role in vascular pathology and are activated by p38 mitogen activated protein kinase (MAPK) dependent mechanisms in many inflammatory settings. Therefore, we investigated whether CRP directly promotes a pro-inflammatory phenotype in human peripheral blood mononuclear cells (HPBMC) via p38 MAPK signaling. CRP exposure leads to a rapid phosphorylation of p38 MAPK in HPBMC. CRP-induced p38 kinase activity in HPBMC was blocked by treatment with an inhibitor of p38 kinase, SD-282. CRP-induced the expression of tissue factor protein and the secretion of IL-6, IL-8, IL-1beta, TNFalpha and PGE(2). Co-exposure to CRP and SD-282 blocked the secretion of these pro-inflammatory and pro-thrombotic mediators. CRP treatment elevated IL-6, IL-8, IL-1beta, TNFalpha, COX-2 and TF mRNA expression. These effects of CRP also required p38 activity, since SD-282 blocked mRNA induction of each. Taken together these data suggest a mechanistic relationship between p38 MAPK signaling and CRP-induced pro-inflammatory and pro-thrombotic activities in HPBMC. Thus, p38 inhibition may represent a novel approach to attenuate inflammation and its consequences in cardiovascular disease.
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PMID:p38 Inhibition attenuates the pro-inflammatory response to C-reactive protein by human peripheral blood mononuclear cells. 1557 41

Platelets may act as inflammatory cells. To study the effects of soluble and cell-bound platelet factors on the expression of several cytokines and related mediators in leukocytes, peripheral blood mononuclear cells (PBMC) were incubated with platelet-free supernatants from SFLLRN-activated platelet-rich plasma (PRP) or SFLLRN-activated PRP in itself. Our main findings were: (i) the gene expression of several chemokines and some cytokines were markedly increased by both activated PRP and supernatants, as also confirmed at the protein level for IL-6, IL-8 and MIP-1alpha; (ii) the selective protein kinase A type I (PKAI) antagonist Rp-8-Br-cAMP reduced this platelet-induced expression of IL-6, IL-8 and MIP-1alpha in PBMC, suggesting a role of cAMP/PKAI mediated mechanisms in this interaction; (iii) PGE(2) dose-dependently increased the release of IL-6, IL-8 and MIP-1alpha from PBMC mimicking the effect of activated platelets. Furthermore, activated platelets released comparable amounts of PGE(2), suggesting that platelet-derived PGE2 could interact with PBMC in co-cultures; (iv) IL-10 inhibited the platelet-inducing effect on IL-6, IL-8 and MIP-1alpha in PBMC, and notably, the addition PGE2 totally abolished this IL-10 effect suggesting that the suppressive effect of IL-10 on the plateletinduced activation of PBMC might at least partly involve PGE(2) related mechanisms. The present study supports a view of platelets as inflammatory cells, and suggests a potential role of platelet-derived PGE(2) in platelet-induced inflammatory responses.
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PMID:Effect of activated platelets on expression of cytokines in peripheral blood mononuclear cells - potential role of prostaglandin E2. 1558 45

To characterize the response of respiratory epithelium to infection by Staphylococcus aureus (S. aureus), human airway cells were incubated for 1 to 24 h with a supernatant of a S. aureus culture (bacterial supernatant), then profiled with a pangenomic DNA microarray. Because an upregulation of many genes was noticed around 3 h, three independent approaches were then used to characterize the host response to a 3-h contact either with bacterial supernatant or with live bacteria: 1) a DNA microarray containing 4,200 sequence-verified probes, 2) a semiquantitative RT-PCR with a set of 537 pairs of validated primers, or 3) ELISA assay of IL-8, IL-6, TNFalpha, and PGE(2). Among others, Fos, Jun, and EGR-1 were upregulated by the bacterial supernatant and by live bacteria. Increased expression of bhlhb2 and Mig-6, promoter regions which harbor HIF responding elements, was explained by an increased expression of the HIF-1alpha protein. Activation of the inducible form of cyclooxygenase, COX-2, and of the interleukins IL-1, IL-6, and IL-8, as well as of the NF-kappaB pathway, was observed preferentially in cells in contact with bacterial supernatant. Early infection was characterized by an upregulation of anti-apoptotic genes and a downregulation of pro-apoptotic genes. This correlated with a necrotic, rather than apoptotic cell death. Overall, this first global description of an airway epithelial infection by S. aureus demonstrates a larger global response to bacterial supernatant (in term of altered genes and variation factors) than to exponentially growing live bacteria.
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PMID:Live Staphylococcus aureus and bacterial soluble factors induce different transcriptional responses in human airway cells. 1559 79

Interleukin-1 (IL-1) plays a crucial role in the immunopathological responses involved with tissue destruction in chronic inflammatory diseases, such as periodontal disease, as it stimulates host cells including fibroblasts to produce various inflammatory mediators and catabolic factors. We comprehensively investigated the involvement of mitogen-activated protein kinases (MAPKs)/activator protein-1 (AP-1) and IkappaB kinases (IKKs)/IkappaBs/nuclear factor-kappaB (NF-kappaB) in IL-1beta-stimulated IL-6, IL-8, prostaglandin E(2) (PGE(2)) and matrix metalloproteinase-1 (MMP-1) production by human gingival fibroblasts (HGF). Three MAPKs, extracellular signal-regulated kinase (ERK), p38 MAPK and c-Jun N-terminal kinase (JNK), which were simultaneously activated by IL-1beta, mediated subsequent c-fos and c-jun mRNA expression and DNA binding of AP-1 at different magnitudes. IKKalpha/beta/IkappaB-alpha/NF-kappaB was also involved in the IL-1 signaling cascade. Further, IL-1beta stimulated HGF to produce IL-6, IL-8, PGE(2) and MMP-1 via activation of the 3 MAPKs and NF-kappaB, as inhibitors of each MAPK and NF-kappaB significantly suppressed the production of IL-1beta-stimulated factors, though these pathways might also play distinct roles in IL-1beta activities. Our results strongly suggest that the MAPKs/AP-1 and IKK/IkappaB/NF-kappaB cascades cooperatively mediate the IL-1beta-stimulated synthesis of IL-6, IL-8, PGE(2) and MMP-1 in HGF.
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PMID:Interleukin-1 stimulates cytokines, prostaglandin E2 and matrix metalloproteinase-1 production via activation of MAPK/AP-1 and NF-kappaB in human gingival fibroblasts. 1565 48

Respiratory epithelial cells are known to contribute to immune responses through the release of mediators. The aim of this study was to characterize the immunomodulatory effects of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco carcinogen, on respiratory epithelial cells and to compare two metabolic pathways, alpha-methylhydroxylation and alpha-methylenehydroxylation, involved in these effects using selective precursors, 4-(acetoxy-methylnitrosamino)-1-(3-pyridil)-1-butanone (NNKOAc) and N-nitroso (acetoxymethyl) methylamine (NDMAOAc), respectively. Human bronchial and alveolar epithelial cell lines, BEAS-2B and A549, respectively, were treated with NNK, NNKOAc and NDMAOAc for 24 h with and without tumour necrosis factor (TNF) and mediators released in cell-free supernatants were measured by enzyme-linked immunosorbent assay (ELISA). NNK significantly inhibited interleukin (IL)-8, IL-6 and monocyte chemoattractant protein-1 (MCP-1) production in both cell types. Similar results were observed with primary bronchial and alveolar epithelial cells. Although NNK increased prostaglandin E(2) (PGE(2)) production by A549 cells, its immunomodulatory effects were not mediated by PGE(2) according to the results with cyclo-oxygenase inhibitors. NNKOAc mimicked NNK effects, whereas NDMAOAc significantly inhibited IL-8 production in BEAS-2B cells and MCP-1 in both cell types. These results demonstrate that NNK and its reactive metabolites have immunosuppressive effects on respiratory epithelial cells, which could contribute to the increased respiratory infections observed in smokers and the development and/or the progression of lung cancer.
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PMID:4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone, a component of tobacco smoke, modulates mediator release from human bronchial and alveolar epithelial cells. 1576 74

15-Deoxy delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), an activator of peroxisome proliferator-activated receptor (PPAR)-gamma and -delta, is a prostanoid metabolite with anti-inflammatory actions. In intrauterine tissues, proinflammatory cytokines and prostaglandins have been identified as playing key roles in the maintenance of pregnancy and the onset of labor. We investigated and compared the early (<3 h) effects of 15d-PGJ(2) with rosiglitazone (PPAR-gamma ligand) and 2-methyl-4-((4-methyl-2-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl)-methylsulfanyl)phenoxy-acetic acid (GW501516) (PPAR-delta ligand) on interleukin (IL)-1beta-induced prostaglandin and cytokine production by amnion-derived WISH cells. We show that 15d-PGJ(2) exerts differential effects depending on concentration. At low concentrations (<0.1 microM), 15d-PGJ(2) inhibited IL-1beta-stimulated prostaglandin E(2) (PGE(2)) but not cytokine (IL-6/IL-8) production or cyclooxygenase-2 (COX-2) expression. This effect was attenuated by a PPAR-gamma inhibitor [2-chloro-5-nitro-N-phenyl-benzamide (GW9662)], by transfection with a dominant-negative PPAR construct, and was reproduced by the PPAR-gamma ligand rosiglitazone. At higher concentrations (1-10 microM), 15d-PGJ(2) inhibited IL-1beta-stimulated PGE(2) and cytokine production and COX-2 expression, and this effect was not blocked by GW9662. Rosiglitazone at high concentrations (1-10 microM) stimulated PGE(2) production in the absence or presence of the dominant-negative PPAR. The PPAR-delta ligand GW501516 also inhibited IL-1beta-stimulated PGE(2) production but only at high concentrations (1 microM). IL-1beta-induced nuclear factor-kappaB (NF-kappaB) DNA binding activity was significantly inhibited by 15d-PGJ(2) (10 microM) and GW501516 (1 microM) but increased with 10 microM rosiglitazone. We conclude that 1) at low concentrations, 15d-PGJ(2) acts through a PPAR-gamma signaling pathway; b) at higher concentrations, its actions are mediated most likely through other pathways such as activation of PPAR-delta and/or inhibition of NF-kappaB; and 3) rosiglitazone exerts PPAR-independent effects at high concentrations (>1 microM).
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PMID:Nanomolar and micromolar effects of 15-deoxy-delta 12,14-prostaglandin J2 on amnion-derived WISH epithelial cells: differential roles of peroxisome proliferator-activated receptors gamma and delta and nuclear factor kappa B. 1582 Nov 50

CD40 is expressed on basal keratinocytes and Squamous Cell Cancer of the Head and Neck (SCCHN) tumor cells in vivo and in vitro. CD40 ligation reduces proliferation of SCCHN cell lines and enhances EGFr mediated inhibition of proliferation. We investigated the mechanisms of CD40 function and EGFr cross-communication in SCCHN cell lines. CD40 ligation inhibited spontaneous and Fas-induced apoptosis. CD40 ligation specifically increased the secretion of IL-8, VEGF and PGE(2) but not IL-6, IL-10, FasL, GM-CSF, or TGFalpha. Co-ligation with EGFr further increased IL-8, VEGF and PGE(2) secretion. CD40 ligation also induced delayed activation and tyrosine phosphorylation of EGFr. CD40 induces secretion of specific proinflammatory and proangiogenic cytokines, inhibits spontaneous and Fas-induced apoptosis and increases EGFr phosphorylation. CD40 signaling may enhance the survival of SCCHN and tumor stroma.
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PMID:CD40 function in squamous cell cancer of the head and neck. 1587 50

Synovial hyperplasia is a hallmark of rheumatoid arthritis (RA) and is regarded as a major destructive element of articular bone and cartilage. This pathological process is accompanied by the production of proinflammatory cytokines, prostaglandin E(2) (PGE(2)), and matrix metalloproteinases (MMPs) in synoviocytes. We studied the spontaneous production of these substances in RA synoviocytes in spheroid culture. Synovial sarcoma cell line SW 982 formed a single spheroid in non-adherent culture plates. It produced interleukin (IL)-1beta, IL-6, IL-8, PGE(2), MMP-2 and MMP-13. Neither the addition of integrin antagonizing oligopeptide (GRGDSP) nor that of vitronectin receptor inhibitor SB-265123 to the culture inhibited any production. Phosphorylation of p38 mitogen-activated protein (MAP) kinase was observed during the culture. A novel p38 MAP kinase inhibitor, R-130823, inhibited the release of IL-6, IL-8 and MMP-13 in a concentration-dependent manner, but not that of IL-1beta or MMP-2. Real-time RT-PCR analysis demonstrated that IL-6, IL-8 and MMP-13 were inhibited at the transcriptional level. R-130823 did not affect the production of PGE(2) in spheroid culture, while the addition of R-130823 suppressed IL-1beta-induced PGE(2) synthesis in monolayer culture of SW 982 cells. The results suggest that spheroid culture induced proinflammatory factors and MMPs in signaling pathways both dependent and independent of p38 MAP kinase.
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PMID:Novel p38 MAP kinase inhibitor R-130823 suppresses IL-6, IL-8 and MMP-13 production in spheroid culture of human synovial sarcoma cell line SW 982. 1588 46


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