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)

Despite a dogma that apoptosis does not induce inflammation, Fas ligand (FasL), a well-known death factor, possesses pro-inflammatory activity. For example, FasL induces nuclear factor kappaB (NF-kappaB) activity and interleukin 8 (IL-8) production by engagement of Fas in human cells. Here, we found that a dominant negative mutant of c-Jun, a component of the activator protein-1 (AP-1) transcription factor, inhibits FasL-induced AP-1 activity and IL-8 production in HEK293 cells. Selective inhibition of AP-1 did not affect NF-kappaB activation and vice versa, indicating that their activations were not sequential events. The FasL-induced AP-1 activation could be inhibited by deleting or introducing the lymphoproliferation (lpr)-type point mutation into the Fas death domain (DD), knocking down the Fas-associated DD protein (FADD), abrogating caspase-8 expression with small interfering RNAs, or using inhibitors for pan-caspase and caspase-8 but not caspase-1 or caspase-3. Furthermore, wildtype, but not a catalytically inactive mutant, of caspase-8 reconstituted the FasL-induced AP-1 activation in caspase-8-deficient cells. Fas ligand induced the phosphorylation of two of the three major mitogen-activated protein kinases (MAPKs): extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) but not p38 MAPK. Unexpectedly, an inhibitor for JNK but not for MAPK/ERK kinase inhibited the FasL-induced AP-1 activation and IL-8 production. These results demonstrate that FasL-induced AP-1 activation is required for optimal IL-8 production, and this process is mediated by FADD, caspase-8, and JNK.
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PMID:Caspase-8- and JNK-dependent AP-1 activation is required for Fas ligand-induced IL-8 production. 1740 42

Transcription nuclear factor-kappaB (NF-kappaB) is hyperactivated in cystic fibrosis (CF) lung epithelial cells, and participates in exaggerated IL-8 production in the CF lung. We recently found that rapid activation of NF-kappaB occurred in a CF lung epithelial IB3-1 cell line (CF cells) upon IL-1beta stimulation, which was not observed in its CFTR-corrected lung epithelial S9 cell line (corrected cells). To test whether other signaling pathways such as that of mitogen-activated protein kinases (MAPKs) could be involved in IL-1beta-induced IL-8 production of CF cells, we investigated ERK1/2, JNK, and p38MAP signaling compared to NF-kappaB. Within 30min, exposure to IL-1beta caused high activation of NF-kappaB, ERK1/2, p38MAP but not JNK in CF cells compared to corrected cells. Treatment of IL-1beta-stimulated CF cells with a series of chemical inhibitors of NF-kappaB, ERK1/2, and p38MAP, when used separately, reduced slightly IL-8 production. However, when used together, these inhibitors caused a blockade in IL-1beta-induced IL-8 production in CF cells. Understanding of the cross-talk between NF-kappaB and MAPKs signaling in CF lung epithelial cells may help in developing new therapeutics to reduce lung inflammation in patients with CF.
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PMID:Enhanced IL-1beta-induced IL-8 production in cystic fibrosis lung epithelial cells is dependent of both mitogen-activated protein kinases and NF-kappaB signaling. 1742 5

Cytokine-induced inflammation is involved in the pathogenesis of type 2 diabetes mellitus (DM). We investigated plasma concentrations and ex vivo production of cytokines and chemokines, and intracellular signalling molecules, mitogen-activated protein kinases (MAPK) in T helper (Th) cells and monocytes in 94 type 2 diabetic patients with or without nephropathy and 20 healthy controls. Plasma concentrations of inflammatory cytokines tumour necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-18 and chemokine CCL2 in patients with diabetic nephropathy (DN) were significantly higher than control subjects, while IL-10, CXCL8, CXCL9, CXCL10 and adiponectin concentrations of DN were significantly higher than patients without diabetic nephropathy (NDN) and control subjects (all P < 0.05). Plasma concentrations of TNF-alpha, IL-6, IL-10, IL-18, CCL2, CXCL8, CXCL9, CXCL10 and adiponectin exhibited significant positive correlation with urine albumin : creatinine ratio in DN patients. The percentage increases of ex vivo production of IL-6, CXCL8, CXCL10, CCL2 and CCL5 upon TNF-alpha activation were significantly higher in both NDN and DN patients than controls (all P < 0.05). The percentage increases in IL-18-induced phosphorylation of extracellular signal-regulated kinase (ERK) in Th cells of NDN and DN were significantly higher than controls (P < 0.05), while the percentage increase in TNF-alpha-induced phosphorylation of p38 MAPK in monocytes and IL-18-induced phosphorylation of p38 MAPK in Th cells and monocytes were significantly higher in NDN patients than controls. These results confirmed that the aberrant production of inflammatory cytokines and chemokines and differential activation of MAPK in different leucocytes are the underlying immunopathological mechanisms of type 2 DM patients with DN.
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PMID:Aberrant activation profile of cytokines and mitogen-activated protein kinases in type 2 diabetic patients with nephropathy. 1742 53

Alpha-galactosylceramide (alpha-GalCer), a bioactive glycolipid isolated from the marine sponge Agelas mauritianus, is a potent immunomodulator with therapeutic potential for the treatment of autoimmune diseases and cancer. The Toll-like receptor 4 (TLR4), one of the promising molecular targets for immune-modulating drugs, is commonly expressed in innate immune cells especially macrophages and dendritic cells. Currently, whether alpha-GalCer can activate TLR4 signaling pathways remains unreported. In this study, we examined the effects of alpha-GalCer and its various structural analogs, CCL-1 approximately 47, on TLR4 activation. We found that one alpha-GalCer analog (CCL-34), but not alpha-GalCer itself, strongly stimulated NF-kappaB activity in RAW 264.7 cells. CCL-34 activated NF-kappaB in a TLR4-dependent manner and stimulated TNF-alpha production in bone marrow cells of TLR4-functional C3H/HeN mice but not in those of TLR4-defective C3H/HeJ mice. Furthermore, CCL-34 treatment stimulated NF-kappaB activation and IL-8 production in a 293 cell line constitutively expressing human TLR4, MD-2 and CD14. Treatment of RAW 264.7 cells with CCL-34 also activated TLR4-downstream mitogen-activated protein kinases (ERK, JNK and p38), induced expression of TLR4-downstream genes (TNF-alpha, IL-6, IL-1beta and iNOS) and promoted production of cytokines characteristic of activated macrophages. CCL-34-treated RAW 264.7 cells acquired a distinct morphology similar to that of LPS-activated macrophages and exhibited higher phagocytotic activity. Moreover, treatment with a TLR4-neutalizing antibody inhibited the CCL-34-induced morphological alteration. In summary, we identify a novel synthetic compound CCL-34 that can activate macrophages via TLR4-dependent signaling pathways. Our results suggest that CCL-34 is an immune modulator and may serve as a potential drug lead for immunotherapy.
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PMID:A synthetic analog of alpha-galactosylceramide induces macrophage activation via the TLR4-signaling pathways. 1744 76

We have shown that the bacterial iron chelator, deferoxamine (DFO), triggers inflammatory signals including the production of CXC chemokine IL-8, in human intestinal epithelial cells (IECs) by activating the ERK1/2 and p38 kinase pathways. In this study we investigated the mechanisms involved in IL-8 generation by DFO, focusing on the transcription factors involved and the roles of both mitogen-activated protein kinases (MAPKs) in the transcription factor activation. Treatment of human epithelial HT-29 cells with DFO markedly up-regulated the expression of the essential components of the transcription factor AP-1 at a transcriptional level, while it minimally affected the expression of the NF-kappaB subunits. DFO also induced AP-1-dependent transcriptional activity in HT-29 cells, and this activity was further augmented by the wild-type c-Jun transfection. In contrast, the AP-1 activity by DFO was markedly decreased by the dominant-negative c-Jun transfection. Electrophoretic mobility shift assays revealed that DFO increases the specific binding of AP-1 but not of NF-kappaB. Such AP-1 binding and transcriptional activities were blocked by the inhibitors of the ERK1/2 and p38 kinase pathways, suggesting that both mitogen-activated protein kinases (MAPKs) lie upstream of AP-1. Besides its action on AP-1, DFO also induced the specific binding of other transcription factors such as CREB and Egr-1. In summary, our results indicate that iron chelator-induced IL-8 generation in IECs involves activation of ERK1/2 and p38 kinase and downstream activation of AP-1. A possible link between iron status and two additional transcription factors, that is, CREB and Egr-1, rather than NF-kappaB, was also suggested.
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PMID:Transcriptional regulation of IL-8 by iron chelator in human epithelial cells is independent from NF-kappaB but involves ERK1/2- and p38 kinase-dependent activation of AP-1. 1747 97

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

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

Peptostreptococcus micros is a Gram-positive anaerobic bacterium associated with periodontitis, a chronic inflammatory disease affecting tooth-supporting tissues. In the present study, we investigated the response of human macrophages to stimulation with a cell wall preparation from P. micros. In addition, the effect of the preparation on the phosphorylation of macrophage kinases was studied. The preparation, which was non-toxic for macrophages, significantly increased the secretion of the pro-inflammatory cytokines TNF-alpha, IL-1beta and IL-6. It also increased the secretion of two potent chemokines IL-8 and, to a lesser extent, RANTES. Lastly, stimulation of macrophages by the P. micros cell wall preparation induced a significant increase in MMP-9 secretion but had no effect on the production of prostaglandin E2. The phosphorylation of macrophage kinases, including cAMP-dependent protein-serine kinase (PKA) catalytic subunit beta, G protein-coupled receptor-serine kinase 2, mitogen-activated protein-serine kinase p38 alpha (p38a MAPK), extracellular regulated protein-serine kinase 2 (ERK2) and Jun N-terminus protein-serine kinases (JNK), increased following stimulation with cell wall. In summary, our study showed that the P. micros cell wall preparation induced intracellular signaling pathways, leading to an increased production of pro-inflammatory cytokines, chemokines and MMP-9 by macrophages.
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PMID:Peptostreptococcus micros cell wall elicits a pro-inflammatory response in human macrophages. 1795 40

Histamine is an important mediator in immune responses, but it is unclear whether periodontal tissues express histamine receptors and are able to respond to histamine. We hypothesized that histamine, inflammatory cytokines, and bacterial components released in inflamed periodontal tissues may be synergistically involved in periodontitis. The present study showed that human gingival fibroblasts mainly express histamine receptor H1R, and responded to histamine to produce interleukin (IL)-8. Stimulation of gingival fibroblasts with tumor necrosis factor-alpha, IL-1alpha, and lipopolysaccharide markedly induced IL-8 production, and the IL-8 production was synergistically augmented in the presence of or pre-treatment with histamine. Selective inhibitors of mitogen-activated protein kinases (MAPKs), nuclear factor (NF)-kappaB, and phospholipase C (PLC) significantly inhibited the synergistic effect. These results indicate that histamine induces IL-8 production from gingival fibroblasts through H1R, and synergistically augments the inflammatory stimuli by amplification of the MAPK and NF-kappaB through H1R-linked PLC. Abbreviations used: HDC, histidine decarboxylase; LPS, lipopolysaccharide; IL, interleukin; TNF, tumor necrosis factor; HR, histamine receptor; PLC, phospholipase C; MAPK, mitogen-activated protein kinase; NF, nuclear factor; ERK, extracellular signal-related kinase; JNK, c-Jun N-terminal kinase; R, receptor; TLR, Toll-like receptor; alpha-MEM, alpha-minimum essential medium; FCS, fetal calf serum; RT-PCR, reverse-transcriptase polymerase chain-reaction; ELISA, enzyme-linked immunosorbent assay; SD, standard deviation; LDH, lactate dehydrogenase.
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PMID:Histamine amplifies immune response of gingival fibroblasts. 1795 1

Fas ligand (FasL) exerts potent proapoptotic and proinflammatory actions on epidermal keratinocytes and has been implicated in the pathogenesis of eczema, toxic epidermal necrolysis, and drug-induced skin eruptions. We used reconstructed human epidermis to investigate the mechanisms of FasL-induced inflammatory responses and their relationships with FasL-triggered caspase activity. Caspase activity was a potent antagonist of the pro-inflammatory gene expression triggered by FasL prior to the onset of cell death. Furthermore, we found that FasL-stimulated autocrine production of epidermal growth factor receptor (EGFR) ligands, and the subsequent activation of EGFR and ERK1 and ERK2 mitogen-activated protein kinases, were obligatory extracellular steps for the FasL-induced expression of a subset of inflammatory mediators, including CXCL8/interleukin (IL)-8, ICAM-1, IL-1alpha, IL-1beta, CCL20/MIP-3alpha, and thymic stromal lymphopoietin. These results expand the known physiological role of EGFR and its ligands from promoting keratinocyte mitogenesis and survival to mediating FasL-induced epidermal inflammation.
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PMID:Fas ligand-induced proinflammatory transcriptional responses in reconstructed human epidermis. Recruitment of the epidermal growth factor receptor and activation of MAP kinases. 1797 27


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