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)

Recent studies have shown that the non-steroidal anti-inflammatory drugs (NSAIDs) activate heat shock transcription factor (HSF1) from a latent cytoplasmic form to a nuclear, DNA binding state. As HSF1 can function as both an activator of heat shock genes and a repressor of non-heat shock genes such as IL1B and c- fos, we have examined the potential role of HSF1 in the effects of NSAIDs on gene expression in a human monocytic cell line THP-1. We found that two members of the NSAIDs, sodium salicylate and sulindac repress the IL1B promoter to similar degree to heat shock or HSF1 overexpression. In addition, sodium salicylate and additional NSAIDs used at concentrations that activate HSF1 also inhibited the expression of other monocytic genes (TNF-alpha, IL-1beta, IL-6, IL-8, IL-10, ICAM-1) activated by exposure to a pro-inflammatory stimulus (lipopolysaccharide, LPS). At least in the case of the IL1B promoter, repression did not seem to involve another factor whose activity is affected by the NSAIDs, NFkappaB as the IL1B promoter fragment used in our studies is not NFkappaB responsive and binds specifically to HSF1. Exposure to NSAIDs had a complex effect on HSP gene expression and while sulindac activated the stress responsive HSP70B promoter, sodium salicylate did not. In addition, only a subset of the NSAIDs induced HSP70 mRNA species. These findings reflect the properties of HSF1 which can be activated to at least two DNA binding forms only one of which activates heat shock promoters and suggest that individual NSAID family members may differentially induce one or other of these forms. Overall therefore, exposure to NSAIDs leads to a profound switch in gene expression in monocytic cells, with suppression of genes involved in macrophage activation and induction of stress genes and HSF1 appears to play a regulatory role in these effects.
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PMID:Non-steroidal anti-inflammatory drugs inhibit the expression of cytokines and induce HSP70 in human monocytes. 1032 74

Heat shock protein (HSP) induction confers protection against diverse forms of cellular and tissue injury. However, the mechanism by which HSP exerts cytoprotective effects is unclear. Because HSP induction inhibits genetic expression of pro-inflammatory cytokines, the transcription of which is dependent on NF-kappa B activation, we explored the relationship between the anti-inflammatory effect of HSP induction and the NF-kappa B/I kappa B alpha pathway. Both HS and sodium arsenite treatment increased HSP70 expression time dependently at mRNA and protein levels. Prior induction of HSP suppressed cytokine-induced IL-8 and TNF-alpha expression at both mRNA and protein levels. Although HSP induction did not affect total cellular expression of NF-kappa B, TNF-alpha-induced increase in NF-kappa B-DNA binding activity and nuclear translocation of the p65 subunit of NF-kappa B were inhibited by prior HSP induction, suggesting that activation of NF-kappa B was blocked. Cytokine-induced I kappa B alpha phosphorylation and its degradation were blocked in HSP-induced cells. Immune complex kinase assays demonstrated that TNF-alpha induced increase in I kappa B kinase activity was suppressed by prior HSP induction. These results suggest that the anti-inflammatory effect of HSP induction in respiratory epithelial cells is related to stabilization of I kappa B alpha, possibly through the prevention of I kappa B kinase activation, which thereby inhibits activation of NF-kappa B.
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PMID:Anti-inflammatory effect of heat shock protein induction is related to stabilization of I kappa B alpha through preventing I kappa B kinase activation in respiratory epithelial cells. 1079 7

Cadmium (Cd) has been regarded as one of the inflammation-related xenobiotics. Cd has been extensively studied in many cellular systems, but a lot of parameters have been evaluated in different experimental conditions. This study was undertaken to examine the effects of low cadmium concentrations in HepG2 cells in the oxidative stress produced, the IL-1beta, tumor necrosis factor (TNF-alpha), IL-6, and IL-8 expression, production of heat shock protein 70 (Hsp70) and the activation of nuclear factors activation protein-1 (AP-1) and NF-kappaB under the same experimental conditions. Also, the participation of TNF-alpha and oxidative stress in AP-1 activation was evaluated. Lipid peroxidation damage increased 1.5 times after the first hour of Cd treatment and increased 1.9 times after 2h. Similar values were maintained until 6h. Reduced glutathione (GSH) diminished 65% after 6h CdCl(2) treatment. N-acetylcysteine (NAC) pre-treatment increased 332% GSH in Cd-treated cells. RNA was isolated from HepG2 cells after 0.5, 1, 3, or 6h incubation with 1, 5, or 10 microM CdCl(2). TNF-alpha and IL-1beta presented a maximum response after 1h treatment, while IL-6 and IL-8 maximum response was after 3h treatment. The Hsp70, determined by Western blot, was constitutively produced, and it increased after 3h Cd treatment. NF-kappaB activation, determined by EMSA, was not increased as a result of Cd treatment. DNA binding of AP-1 was detected and increased, with time up to 4h with an increment of 24 times control value with 5 microM CdCl(2). The HepG2 cells were pretreated with anti-TNF-alpha antibody or 1mM N-acetylcysteine 1h before Cd treatment. Anti-TNF-alpha treatment reduced 67% AP-1 activation, while NAC 47.5%. These data indicate that, Cd-induced TNF-alpha and IL-1beta, that probably, activate AP-1 transcription factor and IL-6 and IL-8 were induced. Anti-TNF-alpha and NAC partially inhibited AP-1 activation. All imply that, a number of factors participate in AP-1 cadmium-induced activation. The Hsp70 is produced by the HepG2 cells after cadmium treatment, and probably has a role in the non-participation of NF-kappaB in the cellular response.
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PMID:Acute cadmium exposure enhances AP-1 DNA binding and induces cytokines expression and heat shock protein 70 in HepG2 cells. 1503 44

Real-time reverse transcriptase polymerase chain reaction (RT rtPCR) was used to quantify the pattern of inflammatory mediator mRNA expression in circulating leukocytes from adult patients diagnosed with severe sepsis. We analysed 29 blood samples from 26 severely septic patients with different septic sources and eight samples from eight healthy adult volunteers. RT rtPCR was used to quantify mRNA expression of 21 different inflammatory mediators in peripheral leukocytes. The median variability in gene expression in the sepsis patients was 10.5 times greater than the variability of the healthy comparison group. We found a significant change in the regulation for the following genes: C5aR (20-fold, P < 0.001), IL-8 (29-fold, P < 0.001), MMP9 (72-fold, P < 0.001), HSP70 (2.4-fold, P = 0.02), and RIP2 (1.8-fold, P < 0.04) were up-regulated. Conversely the median expression of IFNgamma, and IL-6 were zero (P < 0.001), and mtHSP (0.4-fold, P = 0.02) was significantly down-regulated. Using linear discriminant analysis, IFNgamma, IL-12, and TLR4 were correlated to a negative outcome. Different septic sources (peritonitis, burn, pneumonia and musculo-skeletal infections) resulted in significantly different mRNA patterns. The RT rtPCR is a useful tool to monitor the immune response in septic patients. We found a very high variability in inflammatory mediator expression among septic patients compared to healthy volunteers. This suggests that any future immune-modulatory therapy may need to be individualized to the patient's requirements as monitored by RT rtPCR. Different sources of sepsis may result in markedly different activation patterns.
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PMID:The use of real time rtPCR to quantify inflammatory mediator expression in leukocytes from patients with severe sepsis. 1564 82

Primary cultures of normal human airway epithelial cells (NHBE) respond to ambient air pollution particulate matter (PM) by increased production of the cytokine IL-8, and the induction of several oxidant stress response genes. Components of ambient air PM responsible for stimulating epithelial cells have not been conclusively identified, although metal contaminants, benzo[a]pyrene and biological matter have been implicated. Stimulation of IL-8 release from NHBE with coarse (PM(2.5-10)), fine (PM2.5), and UF particle fractions has shown that the coarse particle fraction has the greatest effect on the epithelial cells as well as alveolar macrophages (AM). Since this fraction concentrates fugitive dusts and particle-associated microbial matter, it was hypothesized that NHBE may recognize PM through microbial pattern recognition receptors TLR2 and TLR4, as has been previously shown with AM. NHBE were shown to release IL-8 when exposed to a Gram-positive environmental isolate of Staphylococcus lentus, and lower levels when exposed to Gram-negative Pseudomonas spp. Comparison of TLR2 and TLR4 mRNA expression in NHBE and AM showed that NHBE express similar levels of TLR2 mRNA as the AM, but expressed very low levels of TLR4. When NHBE were stimulated with PM(2.5-10), PM2.5, and UF PM, in the presence or absence of inhibitors of TLR2 and TLR4 activation, a blocking antibody to TLR2 inhibited production of IL-8, while TLR4 antagonist E5531 or the LPS inhibitor Polymixin B had no effect. Furthermore, effects on expression of TLR2 and TLR4 mRNA, as well as the stress protein HSP70 was assessed in NHBE exposed to PM. TLR4 expression was increased in these cells while TLR2 mRNA levels were unchanged. Hsp70 was increased by PM(2.5-10) > PM2.5 > UF PM suggesting the possibility of indirect activation of TLR pathway by this endogenous TLR2/4 agonist.
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PMID:TLR-2 is involved in airway epithelial cell response to air pollution particles. 1569 63

Auto-antibodies against heat shock proteins (HSPs) are frequently found in the sera of patients with rheumatic and other autoimmune diseases. However, it is unclear whether these auto-antibodies play a role in the pathophysiology and etiology of these diseases. We found that a murine anti-HSP60 mAb enhanced the production of IL-8 and tumor necrosis factor-alpha induced by human HSP60 in the human monocytic cell lines THP-1 and U937, and human peripheral blood monocytes. Similar enhancement was observed with the combination of human HSP70 protein and a murine anti-HSP70 mAb. The enhancing effects were also observed for F(ab')2 fragment, but not for monovalent Fab fragment. This suggests that the enhancement is due to cross-linking of HSP by the anti-HSP antibodies. The induction of IL-8 was dramatically suppressed by the transfection of a dominant-negative mutant of Toll-like receptor 4. We also found that sera from patients with rheumatic autoimmune diseases, which contained higher anti-HSP60 auto-antibody titers than sera from healthy donors, significantly enhanced the IL-8 production induced by human HSP60 in THP-1 cells. We propose that auto-antibodies against HSPs have the potential to play a pathogenic role in rheumatic autoimmune diseases by enhancing inflammatory reactions.
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PMID:Anti-HSP auto-antibodies enhance HSP-induced pro-inflammatory cytokine production in human monocytic cells via Toll-like receptors. 1648 40

Oral administration of lactobacilli as probiotics is gaining importance in the treatment of intestinal inflammations. We investigated the effect of non-starter lactobacilli Lactobacillus casei subsp casei 2756, Lactobacillus curvatus 2775, and Lactobacillus plantarum 2142 as well as their spent culture supernatants (SCS) on Salmonella enteritidis 857 growth, interleukin (IL)-8 and heat shock protein 70 (Hsp70) synthesis in undifferentiated crypt-like and differentiated villus-like Caco-2 cells. The cells were infected with graded numbers of non-starter lactobacilli or S. enteritidis 857 for 1 h and allowed to recover for 24 h or exposed to 200 bacteria/cell for 1 h and allowed to recover for different periods of time. In another experiment S. enteritidis 857 was first pre-treated with SCS-lactobacilli for 1 h before infecting the cells. The levels of IL-8 and Hsp70 were assessed using sandwich ELISA and immunostaining of Western blots, respectively. The effect of SCS-lactobacilli on S. enteritidis 857 growth was evaluated by agar plate diffusion test. The non-starter lactobacilli induced a significant increase in the levels of both IL-8 and Hsp70. However, compared with the S. enteritidis 857 induced IL-8 synthesis, the levels of IL-8 induced by the lactobacilli at any equivalent bacterial number were far lower. After exposure of Caco-2 cells to S. enteritidis 857 pre-treated with SCS-lactobacilli, it appeared that their SCS inhibited the S. enteritidis 857 growth and IL-8 synthesis and in addition induced the expression of Hsp70. The differences in response of crypt- and villus-like Caco-2 cells are merely a reflection of their differentiation status. Our data suggest that the beneficial effect of non-starter lactobacilli to the intestinal inflammations might be associated with a decrease of the IL-8 levels. This effect could be mediated, at least in part, by the bacteria themselves or via a secreted antimicrobial product(s) either directly against the pathogens or indirectly through the synthesis of Hsp70.
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PMID:Inhibition of Salmonella-induced IL-8 synthesis and expression of Hsp70 in enterocyte-like Caco-2 cells after exposure to non-starter lactobacilli. 1704 88

Cigarette smoking, a major risk factor for chronic obstructive pulmonary disease, can cause airway inflammation, airway narrowing, and loss of elasticity, leading to chronic airflow limitation. In this report, we sought to define the signaling pathways activated by smoke and to identify molecules responsible for cigarette smoke-induced inflammation. We applied cigarette smoke water extract (CSE) to primary human lung fibroblasts and found that CSE significantly increased CXC chemokine IL-8 production. Meanwhile, 70-kDa heat shock protein (HSP70) was also induced by CSE in a dose- and time-dependent manner. CSE treatment stimulated HSP70 secretion by primary fibroblasts, which augmented IL-8 production. This was further confirmed by exogenously added recombinant HSP70. Using HSP70 small interfering RNA, we confirmed that CSE-induced chemokine production was dependent on heat shock protein expression. Further investigation showed that CSE could also stimulate early growth response-1 (EGR-1) in an ERK-dependent manner and that the expression of HSP70 was EGR-1 dependent. In view of these findings, we hypothesize that the MAPK-EGR-1-HSP70 pathway regulates the cigarette smoke-induced inflammatory process.
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PMID:MAPK pathway mediates EGR-1-HSP70-dependent cigarette smoke-induced chemokine production. 1749 53

Stressed cells undergoing necrosis release molecules that acts as endogenous danger signals to alert and activate innate immune cells. Both HMGB1 and HSP70 are induced in activated monocytes/macrophages and also are released from stressed or injured cells. We investigated whether HMGB1 and HSP70 released from necrotic monocytes/macrophages, can act as danger signals to mediate proinflammatory cytokine responses to bacterial endotoxin or lipopolysaccharide (LPS). We show that cell lysate, obtained from necrotic cells directly stimulates the proinflammatory cytokine and chemokine responses in human monocyte/macrophage cell line, THP-1, as revealed by the induction of TNF-alpha, IL-6 and IL-8 mRNA expression and protein production. In the presence of LPS, necrotic cell lysate induced a more robust increase in all three proteins. We found that HMGB1 and HSP70 were indeed present in the necrotic cell lysate and were responsible for the significant induction of the proinflammatory cytokine expression, as neutralization with antibodies against both proteins blocked the increase in the cytokine production seen after incubating LPS-stimulated cells with the necrotic cell lysate. We also found that the newly identified triggering receptor expressed on myeloid cells-1 (TREM-1) was involved in mediating the HMGB1- and HSP70-induced cytokine production. Blocking TREM-1 on THP-1 cells with a recombinant chimera prevented the increase in cytokine production, while simultaneous blocking of TLR4 and TREM-1 completely abolished the proinflammatory response, suggesting that TREM-1 synergizes with TLR4 to mediate the effects of such signals from necrotic cells. In addition, blocking HMGB1 or HSP70 simultaneously with TREM-1 did not decrease the cytokine level further, confirming the involvement of TREM-1 in mediating the effect of HMGB1 and HSP70. Although the interaction of HMGB1 and HSP70 with TREM-1 induced I kappa B alpha and p38 expression, both of which are required for the inflammatory cytokine expression, blockade of TREM-1 did not affect I kappa B alpha expression but markedly reduced p38 activation, as revealed by Western blot analysis. Together, these results demonstrate that HMGB1 and HSP70 released from necrotic cells function as endogenous danger signals to augment the proinflammatory responses in monocytes/macrophage and that TREM-1 relays such signals to the cytokine expression cascade. This mechanism may contribute to the amplification and persistence of the inflammatory response to bacterial infection.
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PMID:Endogenous signals released from necrotic cells augment inflammatory responses to bacterial endotoxin. 1756 91

Ambient particulate matter (PM) induces adverse health effects through the ability of pro-oxidative chemicals to induce the production of oxygen radicals and oxidant injury. Utilizing a proteomics strategy involving 2-D DIGE, immunoblotting, and real-time PCR, we demonstrate that organic diesel exhaust particle (DEP) chemicals induce an unfolding protein response (UPR) and proinflammatory effects in the human bronchial epithelial cell line, BEAS-2B. DIGE and MS showed the induction of at least 14 proteins, among which heat shock protein 70 (HSP70), HSP40, TPR2, and T-complex protein 1 (zeta-subunit) are known to play a role in the UPR. Demonstrating increased HSP70 mRNA expression and nuclear translocation of HSF1, the key transcription factor responsible for HSP expression, further strengthened this notion. Immunoblotting demonstrated increased expression of ATF4, an ER stress-associated transcriptional enhancer responsible for differential protein translation under conditions of ER stress. Finally, the DEP extract induced the expression of IL-6 and IL-8 in the culture supernatant. The role of oxidative stress was demonstrated further by response subtraction in the presence of the thiol antioxidant, N-acetyl cysteine. Our data suggest that pro-oxidative DEP chemicals induce protein unfolding/misfolding that lead to UPR and proinflammatory effects in a cell type that is targeted by PM in the lung.
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PMID:Pro-oxidative DEP chemicals induce heat shock proteins and an unfolding protein response in a bronchial epithelial cell line as determined by DIGE analysis. 1792 15


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