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)

Previous studies have demonstrated that neutrophils possess an active serine protease(s) which may be involved in the process of chemotaxis but the precise identity of this enzyme(s) remains to be determined. In this study fourteen different protease inhibitors were tested over a wide concentration range for their ability to inhibit unstimulated neutrophil movement and chemotaxis to C5a, fMLP and IL-8. Pretreatment of neutrophils with aspartyl or metallo-protease inhibitors had no effect on either chemotaxis or random cell movement. The thiol protease inhibitors E-64 and cystatin, as well as the thiol/serine inhibitors antipain and leupeptin, diminished only C5a-induced chemotaxis. Pretreatment of neutrophils with the serine protease inhibitors PMSF or 3,4-DCI significantly reduced chemotaxis to C5a, fMLP and IL-8. The inhibitor of trypsin-like serine proteases, TLCK, and the neutrophil elastase inhibitor MeO-Suc-AAPV-CMK had no inhibitory effect on cell movement. However, two different inhibitors of chymotrypsin-like serine proteases, TPCK and chymostatin, significantly inhibited movement to any chemoattractant. These results suggest that an active chymotrypsin-like serine protease is essential for neutrophils to respond to chemotactic stimuli.
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PMID:Inhibition of neutrophil chemotaxis by protease inhibitors. Differential effect of inhibitors of serine and thiol proteases. 854 71

Chemokines may regulate the process of immune cell infiltration that is often found in pancreatic cancer. In this study, we investigated the secretion of the chemokines [interleukin (IL)-8, monocyte chemoattractant protein (MCP)-1, and RANTES (regulated on activation, normal T cell expressed and secreted)] in human pancreatic cancer cell lines. The chemokine secretion in three pancreatic cancer cell lines (PANC-1, MIA PaCa-2, and BxPC-3) was evaluated by enzyme-linked immunosorbent assay (ELISA) and Northern blot, and the activation of nuclear factor-kappaB (NF-kappaB) and NF-IL6 was assessed by an electrophoretic gel mobility shift assay (EMSA). Without any stimulation, IL-8 secretion was detected in all cell lines, and MCP-1 secretion was detected in PANC-1 and MIA PaCa-2 cells. However, RANTES secretion was not detected in all cells. The addition of IL-1beta and tumor necrosis factor (TNF)-alpha strongly enhanced IL-8, MCP-1, and RANTES secretion; these responses were observed at the mRNA level as well as at the protein level. IL-1beta and TNF-alpha induced a rapid activation of nuclear factor (NF)-kappaB in PANC-1 cells, and the increase in chemokine mRNA expression correlated with NF-kappaB activation. The activation of NF-IL6 was modest. A blockade of NF-kappaB activation by TPCK markedly reduced the IL-1beta- and TNF-alpha-induced chemokine gene expression. Our findings indicate that chemokines are produced by pancreatic cancer cells, and suggest that these factors may contribute to the accumulation of tumor-associated immune cells. In addition, the transcriptional activation of chemokine genes in pancreatic cancer cells may be closely associated with NF-kappaB activation.
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PMID:The expression of chemokine genes correlates with nuclear factor-kappaB activation in human pancreatic cancer cell lines. 1088 30

Epithelial cells are the first cells that encounter infecting bacteria and, as such, they have developed several mechanisms for microbial protection. We have shown previously that bladder epithelial cells express the lipopolysaccharide (LPS) receptor Toll-like receptor (TLR) 4 that enables a rapid cellular interleukin (IL)-8 response when exposed to Escherichia coli and LPS. TLR4 belongs to a family of receptors that was initially identified in Drosophila, in which Toll is required for the immune response against fungi. Fungal exposure activates a series of serine proteases that process the protein Spaetzle to a cytokine-like form that acts as a ligand for Toll. Here, we investigated whether a similar proteolytic cascade is required for human TLR activation. When screening a set of 18 protease inhibitors, three serine protease inhibitors (TPCK, TLCK and Pefabloc) were shown to inhibit LPS- and peptidoglycan-induced IL-8 production in TLR2- and TLR4-positive bladder epithelial cells. However, they were equally effective inhibitors of IL-1beta-induced signalling, indicating that their target(s) is/are located downstream of the TLRs. Further characterization showed that these inhibitors blocked I kappa B degradation but not phosphorylation in LPS-stimulated cells, which suggests that the serine protease inhibitors target the 26S proteasome. Identical results were obtained on LPS-stimulated monocytes. Based on these data, we find no evidence for the involvement of proteases upstream of TLRs in either epithelial cells or cells of the monocytic lineage.
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PMID:TLR4-dependent lipopolysaccharide signalling in epithelial cells is independent of extracellular protease activity. 1202 57

We have previously demonstrated that chloroquine may evoke inflammatory responses in the central nervous system by inducing expression of pro-inflammatory cytokines by astroglial cells. In this study, we further examined the molecular mechanism responsible for chloroquine-induced activation of NF-kappaB and subsequent expression of chemokines by astroglial cells. We observed that (1) chloroquine induced expression of chemokines such as CCL2 and CXCL8 in a dose- and time-dependent manner in human astroglial cells; (2) other lysosomotropic agents such as ammonium chloride and bafilomycin A1 had minimal effects on chemokine expression; (3) inhibition of NF-kappaB by MG-132 and TPCK suppressed chloroquine-induced mRNA expression of chemokines; (4) chloroquine increased the intracellular level of reactive oxygen species (ROS) in a dose- and time-dependent manner by human astroglial cells, but not by monocytic/microglial cells; (5) chloroquine-induced increase of intracellular ROS level was suppressed by pre-incubation with diphenyl iodonium (DPI) and N-acetyl cysteine (NAC); and (6) inhibition of chloroquine-induced ROS production by DPI or NAC suppressed chloroquine-mediated activation of NF-kappaB and subsequent mRNA expression of chemokines in astroglial cells. These results collectively suggest that chloroquine generates ROS, which is responsible for NF-kappaB activation and subsequent expression of pro-inflammatory chemokines in human astroglial cells.
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PMID:Reactive oxygen species mediate chloroquine-induced expression of chemokines by human astroglial cells. 1513 8

A purified recombinant spike (S) protein was studied for its effect on stimulating human peripheral blood monocyte macrophages (PBMC). We examined inflammatory gene mRNA abundances found in S protein-treated PBMC using gene arrays. We identified differential mRNA abundances of genes with functional properties associated with antiviral (CXCL10) and inflammatory (IL-6 and IL-8) responses. We confirmed cytokine mRNA increases by real-time quantitative(q) RT-PCR or ELISA. We further analyzed the sensitivity and specificity of the prominent IL-8 response. By real-time qRT-PCR, S protein was shown to stimulate IL-8 mRNA accumulation in a dose dependent manner while treatment with E protein did not. Also, titration of S protein-specific production and secretion of IL-8 by ELISA showed that the dose of 5.6nM of S produced a significant increase in IL-8 (p=0.003) compared to mock-treated controls. The increase in IL-8 stimulated by a concentration of 5.6nM of S was comparable to concentrations seen for S protein binding to ACE2 or to neutralizing monoclonal antibody suggesting a physiological relevance. An NF-kappaB inhibitor, TPCK (N-Tosyl-L-Phenylalanine Chloromethyl Ketone) could suppress IL-8 production and secretion in response to S protein in PBMC and THP-1 cells and in HCoV-229E virus-infected PBMC. Activation and translocation of NF-kappaB was shown to occur rapidly following exposure of PBMC or THP-1 cells to S protein using a highly sensitive assay for active nuclear NF-kappaB p65 transcription factor. The results further suggested that released or secreted S protein could activate blood monocytes through recognition by toll-like receptor (TLR)2 ligand.
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PMID:SARS coronavirus spike protein-induced innate immune response occurs via activation of the NF-kappaB pathway in human monocyte macrophages in vitro. 1918 96