UNIPROT:P10145 - FACTA Search

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Query: UNIPROT:P10145 (IL-8)
23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-31 (IL-31) is a novel T-helper-lymphocyte-derived cytokine that plays an important role in allergic skin inflammation and atopic dermatitis. It has recently been implicated in bronchial inflammation. We investigated the functions and mechanisms of IL-31-induced activation of human bronchial epithelial cells. The gene and protein expressions of candidate cytokines/chemokines from IL-31-stimulated human bronchial epithelial BEAS-2B cells were first quantified by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The activity of different mitogen-activated protein kinases (MAPKs) in IL-31-stimulated BEAS-2B cells was assessed by Western blot. The IL-31 could significantly elevate the gene and protein expressions of epidermal growth factor (EGF), vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein-1 (MCP-1/CCL2) of BEAS-2B cells in both time-dependently and dose-dependently. Combination of IL-31 with either IL-4 or IL-13 further enhanced VEGF and CCL2 production while IL-31 could synergistically augment the release of EGF, VEGF, CCL2, IL-6 and IL-8 in cocultures of BEAS-2B cells and eosinophils. In addition, IL-31 could activate p38 MAPK, extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) of BEAS-2B cells. Selective inhibitors of p38 MAPK (SB203580), ERK (PD98059), and JNK (SP600125) could differentially inhibit the production of EGF, VEGF and CCL2, thereby suggesting a role for MAPKs in IL-31 functions. In conclusion, the activation of MAPKs can be crucial for IL-31-mediated activation of bronchial epithelial cells, thereby providing an immunological role for IL-31 in bronchial inflammation, at least partly, via epithelial EGF, VEGF and CCL2 production.
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PMID:Interleukin-31 induces cytokine and chemokine production from human bronchial epithelial cells through activation of mitogen-activated protein kinase signalling pathways: implications for the allergic response. 1762 70

The citrus unshiu peel has been used traditionally as a medicine to improve bronchial and asthmatic conditions or cardiac and blood circulation in Korea, China, and Japan. Here, we report the effects of citrus unshiu peel water extract (CPWE) on the phorbol myristate acetate (PMA)+calcium ionophore A23187-induced hypoxia-inducible factor-1alpha (HIF-1alpha) activation and inflammatory cytokine production from the human mast cell line, HMC-1 cells. We compared CPWE with hesperidin, a common constituent of citrus unshiu. CPWE and hesperidin inhibited the PMA+A23187-induced HIF-1alpha expression and the subsequent production of vascular endothelial growth factor (VEGF). In addition, CPWE suppressed PMA+A23187-induced phosphorylation of the extracellular signal-regulated kinase (ERK). We also show that the increased cytokines interleukin (IL)-1beta, IL-8, and tumor necrosis factor (TNF)-alpha level was significantly inhibited by treatment of CPWE or hesperidin. In the present study, we report that CPWE and hesperidin are inhibitors of HIF-1alpha and cytokines on the mast cell-mediated inflammatory responses.
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PMID:Hesperidin inhibits expression of hypoxia inducible factor-1 alpha and inflammatory cytokine production from mast cells. 1762 75

Molecular abnormalities in the epithelial cells of endometriosis and their relevance to carcinogenesis of the ovary have been well studied. On the other hand, the differences of proinflammatory microenvironments between endometriosis and ovarian carcinomas have not been well documented yet. In this study, the expression patterns of CXC chemokines (IL-8, ENA-78, GRO-alpha, I-TAC, Mig, and SDF-1) and their receptors (CXCR2, CXCR3, and CXCR4) were compared among 12 ovarian carcinomas, 8 endometriosis, and 6 normal ovaries using quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry. The CXCR3-mediated signaling in ovarian carcinoma cells in vitro was also investigated. In quantitative reverse transcriptase polymerase chain reaction, ENA-78 was up-regulated both in endometriosis and carcinomas, whereas I-TAC was detected exclusively in carcinomas. CXCR3 was up-regulated both in carcinomas and endometriosis. However, immunohistochemical studies revealed that the localization of CXCR3 in carcinomas was distinctively different from that in endometriosis. In carcinoma-endometriosis coexisting cases, CXCR3-positive lymphocytes in benign lesions decreased in proportion as CXCR3-positive tumor cells replaced the tissues. CXCR3 was also detected in ovarian carcinoma cell lines in vitro. Administration of interferon gamma (IFN-gamma)-inducible chemokines induced extracellular signal-regulated kinase phosphorylation in these carcinoma cells. The results indicated that CXC chemokines might contribute to the progression of ovarian carcinomas and endometriosis in different manners. Aberrant expression of IFN-gamma-inducible chemokines and CXCR3 in carcinoma cells in association with reduced CXCR3-positive immune cells raised the possibility that IFN-gamma-inducible chemokines might not exert effective antitumor immune responses but that they might work in favor of tumor progression.
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PMID:Up-regulation of CXC chemokines and their receptors: implications for proinflammatory microenvironments of ovarian carcinomas and endometriosis. 1770 63

Human neutrophil peptides (HNP) kill microorganisms but also modulate immune responses through upregulation of the chemokine IL-8 by activation of the nucleotide P2Y(6) receptor. However, the intracellular signaling mechanisms remain yet to be determined. Human lung epithelial cells (A549) and monocytes (U937) were stimulated with HNP in the absence and presence of the specific kinase inhibitors for Src, extracellular signal-regulated kinase-1 and -2 (ERK1/2), p38 mitogen-activated protein kinase (MAPK), c-Jun-N-terminal kinases (JNK), and Akt. HNP induced a rapid phosphorylation of the kinases in both cell types associated with a dose-dependent, selective production of IL-8 among 10 cytokines assayed. The HNP-induced IL-8 production was blocked by the Src tyrosine kinase inhibitor PP2, MEK1/2 inhibitor U0126, and the phosphatidylinositol 3 kinase (PI3K) inhibitor LY294002, but not by the JNK inhibitor SP600125 in both cell types. Treatment with the p38 inhibitor SB203580 attenuated the HNP-induced IL-8 production only in monocytes. Blockade of Src kinase blunted HNP-induced phosphorylation of the ERK1/2 and Akt but not p38 in monocytes. In contrast, Src inhibition had no effect on phosphorylation of the other kinases in the lung epithelial cells. We conclude that the activation of ERK1/2 and PI3K/Akt pathways is required for HNP-induced IL-8 release which occurs in a Src-independent manner in lung epithelial cells, while is Src-dependent in monocytes.
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PMID:Differential signaling mechanisms of HNP-induced IL-8 production in human lung epithelial cells and monocytes. 1778 63

Macrophages release cytokines that may contribute to the chronic inflammation observed in pulmonary conditions such as asthma and chronic obstructive pulmonary disease. Thus, inhibition of macrophage cytokine production may have a therapeutic benefit. Human lung macrophages are a rich source of the proinflammatory cytokines, tumor necrosis factor (TNF)-alpha, granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-6, and IL-8, that are elevated in the bronchoalveolar lavage and sputum of subjects with respiratory diseases. Cytokine production from both monocytes and macrophages is mediated by mitogen-activated protein kinase (MAPK) pathways. This study compared the effects of a novel p38 MAPK inhibitor, N-cyano-N'-(2-{[8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl)-guanidine (PCG), and an extracellular signal-regulated kinase (ERK) pathway inhibitor, 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD098059), on cytokine release from lipopolysaccharide (LPS)-stimulated human monocytes, monocyte-derived macrophages (MDM), and lung macrophages. Lung macrophages, MDM, and monocytes were stimulated with LPS, and cytokine release was measured by enzyme-linked immunosorbent assay. Immunoblots were performed to confirm p38 and ERK1/2 MAPK expression and activity. PCG inhibited TNF-alpha release more effectively from monocytes compared with MDM or macrophages (maximal inhibition was 99.3 +/- 1.4, 62.7 +/- 4.3, and 58.6 +/- 6.6%, respectively; n = 7-9). PD098059 was less effective at suppressing TNF-alpha release from monocytes compared with MDM and lung macrophages (maximal inhibition was 37.4 +/- 2.8, 70.1 +/- 4.5, and 68.7 +/- 5.1%, respectively; n = 7-9). The pattern of GM-CSF, IL-6, and IL-8 release was comparable with that of TNF-alpha. These data suggest a differential involvement for each of these MAPK pathways in macrophage cytokine production compared with monocytes.
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PMID:Different mitogen-activated protein kinase-dependent cytokine responses in cells of the monocyte lineage. 1792 Nov 89

Cystic fibrosis (CF) is a lethal disease caused by defective function of the cftr gene product, the CF transmembrane conductance regulator (CFTR) that leads to oxidative damage and excessive inflammatory response in lungs of CF patients. We here report the effects of oxidative stress (hyperoxia, 95% O(2)) on the expression of pro-inflammatory interleukin (IL)-8 and CXCR1/2 receptors in two human CF lung epithelial cell lines (IB3-1, with the heterozygous F508del/W1282X mutation and CFBE41o- with the homozygous F508del/F508del mutation) and two control non-CF lung epithelial cell lines (S9 cell line derived from IB3-1 after correction with wtCFTR and the normal bronchial cell line 16HBE14o-). Under oxidative stress, the expression of IL-8 and CXCR1/2 receptors was increased in CF, corrected and normal lung cell lines. The effects of oxidative stress were also investigated by measuring the transcription nuclear factor kappaB (NF-kappaB) and activator protein-1 (AP-1) activities. Under oxidative stress, no increase of NF-kappaB activation was observed in CF lung cells in contrast to that observed in normal and corrected CF lung cells. The signalling of mitogen-activated protein (MAP) kinases was further studied. We demonstrated that extracellular signal-regulated kinase (ERK1/2) and AP-1 activity was markedly enhanced in CF but not non-CF lung cells under oxidative stress. Consistently, inhibition of ERK1/2 in oxidative stress-exposed CF lung cells strongly decreased both the IL-8 production and CXCR1/2 expression. Therefore, targeting of ERK1/2 MAP kinase may be critical to reduce oxidative stress-mediated inflammation in lungs of CF patients.
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PMID:Oxidative stress induces extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase in cystic fibrosis lung epithelial cells: Potential mechanism for excessive IL-8 expression. 1793 67

Inflammation, elicited in the skin following tissue damage or pathogen invasion, may become chronic with deleterious consequences. Tumor necrosis factor (TNF) is a key mediator of cutaneous inflammation and the keratinocyte an important protagonist of skin immunity. Calcitriol, the hormonally active vitamin D metabolite, and its analogs attenuate epidermal inflammation and inhibit the hyperproliferation of keratinocytes associated with the inflammatory disorder, psoriasis. Since activation of extracellular signal-regulated kinase (ERK) promotes keratinocyte proliferation and mediates epidermal inflammation, we studied the effect of calcitriol on ERK activation in HaCaT keratinocytes exposed to the ubiquitous inflammatory cytokine TNF. By using the EGF receptor (EGFR) tyrosine kinase inhibitor, AG1487 and the Src family inhibitor, PP-1, we established that TNF activated ERK in an EGFR and Src dependent and an EGFR and Src independent modes. EGFR dependent activation resulted in the upregulation of the transcription factor, c-Fos, while the EGFR independent activation mode was of a shorter duration, did not affect c-Fos expression but induced IL-8 mRNA expression. Pretreatment with calcitriol, enhanced TNF-induced EGFR-Src dependent ERK activation and tyrosine phosphorylation of the EGFR, but abolished the EGFR-Src independent ERK activation. These effects were mirrored by enhancement of c-Fos and inhibition of IL-8 induction by TNF. Treatment with calcitriol increased the rate of the de-phosphorylation of activated ERK, accounting for the inhibition of EGFR-Src independent ERK activation by TNF. It is possible that effects on the ERK cascade contribute to the effects of calcitriol and its synthetic analogs on cutaneous inflammation and keratinocyte proliferation.
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PMID:Two modes of ERK activation by TNF in keratinocytes: different cellular outcomes and bi-directional modulation by vitamin D. 1808 Mar 20

As effector cells in host defence, neutrophils actively destroy invading microorganisms via a potent antimicrobial arsenal composed of oxidants and antimicrobial peptides. Psoriasin, an Escherichia coli-cidal antimicrobial protein, has been found to be overexpressed in psoriasis, a skin disease characterized by infiltration of neutrophils. In addition to its microbicidal activities and chemotaxis of neutrophils reported previously, we hypothesized that psoriasin might regulate other neutrophil functions such as cytokine and chemokine production, reactive oxygen species generation, and release of antimicrobial peptides. In the current study, we demonstrate that psoriasin activates neutrophils to produce a range of cytokines and chemokines including interleukin-6 (IL-6), IL-8/CXCL8, tumour necrosis factor-alpha, macrophage inflammatory protein-1alpha (MIP-1alpha)/CCL3, MIP-1beta/CCL4 and MIP-3alpha/CCL20. Furthermore, psoriasin induces phosphorylation of mitogen-activated protein kinase p38 and extracellular signal-regulated kinase (ERK), but not c-Jun N-terminal kinase (JNK), both of which are required for the production of cytokines and chemokines as evidenced by the inhibitory effects of p38 and ERK inhibitors on psoriasin-mediated neutrophil activation. Moreover, psoriasin stimulates the generation of reactive oxygen species from neutrophils, most likely via nicotinamide adenine dinucleotide phosphate oxidase activation. Finally, we demonstrate that psoriasin enhances messenger RNA expression of alpha-defensins, termed human neutrophil peptides (HNP) 1 to 3, and induces their extracellular release. Besides its antimicrobial properties, therefore, psoriasin may contribute to innate immunity through enhancing neutrophil host defence functions at sites of inflammation or infection.
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PMID:Microbicidal protein psoriasin is a multifunctional modulator of neutrophil activation. 1819 66

Tumor necrosis factor (TNF)-alpha is central to the endometriotic disease process. TNF-alpha receptor signaling regulates epithelial cell secretion of inflammation and invasion mediators. Because epithelial cells are a disease-inducing component of the endometriotic lesion, we explored the response of 12Z immortalized human epithelial endometriotic cells to TNF-alpha. This report reveals the impact of disruption of established TNF-alpha-induced signaling cascades on the expression of biomarkers of inflammation and epithelial-mesenchymal transition (EMT) from endometriotic epithelial cells. Note that we show the molecular potential of soluble TNF-R1 [TNF binding protein (TBP)] and a panel of small molecule kinase inhibitors to block endometriotic gene expression directly. The TNF-alpha receptor is demonstrated to signal through IkappaB kinase complex (IKK) 2 > IkappaB > nuclear factor kappaB, extracellular signal-regulated kinase > mitogen-activated protein kinase kinase (MEK), p38, and phosphatidylinositol 3-kinase (PI3K) > Akt1/2. TNF-alpha induces the expression of transcripts for inflammatory mediators interleukin (IL)-6, IL-8, regulated on activation normal T cell expressed and secreted, TNF-alpha, granulocyte macrophage-colony-stimulating factor (GM-CSF), and monocyte chemoattractant protein (MCP)-1 and also invasion mediators matrix metalloproteinase (MMP)-7, MMP-9, and intracellular adhesion molecule-1. Indeed, TBP inhibits the TNF-alpha-induced expression of all the above endometriotic genes in 12Z endometriotic epithelial cells. The secretion of IL-6, IL-8, GMCSF, and MCP-1 by TNF-alpha is blocked by TBP. Interestingly, MEK, p38, and IKK inhibitors block TNF-alpha-induced IL-8, IL-6, and GM-CSF secretion and 12z invasion, whereas the PI3K inhibitors do not. The only inhibitor to block MCP-1 expression is the p38 inhibitor. Last, TBP, MEK inhibitor, or p38 inhibitor also block cell surface expression of N-cadherin, a marker of mesenchymal cells. Taken together, these results demonstrate that interruption of TNF-alpha-induced signaling pathways in human endometriotic epithelial cells results in decreased expression and secretion of biomarkers for inflammation, EMT, and disease progression.
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PMID:Tumor necrosis factor-alpha regulates inflammatory and mesenchymal responses via mitogen-activated protein kinase kinase, p38, and nuclear factor kappaB in human endometriotic epithelial cells. 1825 6

Interleukin-8 (IL-8) is associated with tumorigenesis by promoting angiogenesis and metastasis. Although up-regulation of IL-8 is indicated in many cancers, its function in pancreatic cancer has not been well characterized. In this study we examined the expression of IL-8 on pancreatic cancer cells and clinical tissue specimens, and investigated the effect of exogenous IL-8 on gene expression, and signaling in human pancreatic cancer cells. We found that pancreatic cancer cells expressed higher amount of IL-8 mRNA than normal human pancreatic ductal epithelium cells. IL-8 mRNA was also substantially overexpressed in 11 of 14 (79%) clinical pancreatic-adenocarcinoma samples compared with that in their surrounding normal tissues. Exogenous IL-8 up-regulated the expression of vascular endothelial growth factor(165), and neuropilin (NRP)-2 in BxPC-3 cells, one of human pancreatic cancer cell lines. IL-8 expression was inducible by hypoxia mimicking reagent cobalt chloride. In addition, IL-8 activated extracellular signal-regulated kinase (ERK)1/2 signaling pathway in BxPC-3 cells. Our studies suggest that IL-8 might be a malignant factor in human pancreatic cancer by induction of vascular endothelial growth factor and NRP-2 expression and ERK activation. Targeting IL-8 along with other antiangiogenesis therapy could be an effective treatment for this malignancy.
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PMID:Interleukin-8 increases vascular endothelial growth factor and neuropilin expression and stimulates ERK activation in human pancreatic cancer. 1830 36

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