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)

Cystic fibrosis (CF) lung disease is characterized by infection with Pseudomonas aeruginosa and a sustained accumulation of neutrophils. In this study, we analyzed 1) the expression of MyD88-dependent TLRs on circulating and airway neutrophils in P. aeruginosa-infected CF patients, P. aeruginosa-infected non-CF bronchiectasis patients, and noninfected healthy control subjects and 2) studied the regulation of TLR expression and functionality on neutrophils in vitro. TLR2, TLR4, TLR5, and TLR9 expression was increased on airway neutrophils compared with circulating neutrophils in CF and bronchiectasis patients. On airway neutrophils, TLR5 was the only TLR that was significantly higher expressed in CF patients compared with bronchiectasis patients and healthy controls. Studies using confocal microscopy and flow cytometry revealed that TLR5 was stored intracellularly in neutrophils and was mobilized to the cell surface in a protein synthesis-independent manner through protein kinase C activation or after stimulation with TLR ligands and cytokines characteristic of the CF airway microenvironment. The most potent stimulator of TLR5 expression was the bacterial lipoprotein Pam(3)CSK(4). Ab-blocking experiments revealed that the effect of Pam(3)CSK(4) was mediated through cooperation of TLR1 and TLR2 signaling. TLR5 activation enhanced the phagocytic capacity and the respiratory burst activity of neutrophils, which was mediated, at least partially, via a stimulation of IL-8 production and CXCR1 signaling. This study demonstrates a novel mechanism of TLR regulation in neutrophils and suggests a critical role for TLR5 in neutrophil-P. aeruginosa interactions in CF lung disease.
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PMID:TLR expression on neutrophils at the pulmonary site of infection: TLR1/TLR2-mediated up-regulation of TLR5 expression in cystic fibrosis lung disease. 1868 66

Experimental exposure of swine to highly virulent classical swine fever virus (CSFV) strain Brescia causes an invariably fatal disease of all infected animals by 8-14 days post-infection. Host mechanisms involved in this severe outcome of infection have not been clearly established. To understand these mechanisms, we analyzed the response of primary cultured swine macrophages, a CSFV primary target cell, to infection with Brescia strain. Steady state levels of mRNA accumulation were assessed for 58 genes involved in modulation of the host immune response, at 24 and 48 h post-infection (hpi), by means of quantitative reverse transcription real-time PCR analysis (qrt-PCR). Eighteen genes showed altered expression upon infection with CSFV strain Brescia including: cytokines (IL-1alpha, IL-1beta, IL-6, and IL-12p35); cytokine receptors (IL-2Ralpha, IL-12Rbeta, and TGF-betaIIIR); chemokines (IL-8, AMCF-1, AMCF-2, MCP-2, and RANTES); interferons (INFalpha and INFbeta); and toll-like receptors (TLR3, TLR5, TLR9, and TLR10). Although these genes are associated with mechanisms of innate immune response and antiviral activity, their altered expression does not curtail CSFV Brescia growth kinetics and virus yield in swine macrophages. Data gathered here suggests that the observed gene expression profile might explain immunological and pathological changes associated with virulent CSFV infections.
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PMID:Patterns of cellular gene expression in swine macrophages infected with highly virulent classical swine fever virus strain Brescia. 1879 18

In vitro organ culture (IVOC) represents a gold standard model to study enteropathogenic E. coli (EPEC) infection of human intestinal mucosa. However, the optimal examination of the bacterial-host cell interaction requires a directional epithelial exposure, without serosal or cut surface stimulation. A polarized IVOC system (pIVOC) was developed in order to overcome such limitations: apical EPEC infection produced negligible bacterial leakage via biopsy edges, resulted in enhanced colonization compared with standard IVOC, and showed evidence of bacterial detachment, as in natural rabbit EPEC infections. Examination of mucosal innate immune responses in pIVOC showed both interleukin (IL)-8 mRNA and protein levels were significantly increased after apical EPEC infection. Increased IL-8 levels mainly depended on flagellin expression as fliC-negative EPEC did not elicit a significant IL-8 response despite increased mucosal colonization compared with wild-type EPEC. In addition, apical application of purified flagella significantly increased IL-8 protein levels over non-infected controls. Immunofluorescence staining of EPEC-infected small intestinal biopsies revealed apical and basolateral distribution of Toll-like receptor (TLR) 5 on epithelium, suggesting that EPEC can trigger mucosal IL-8 responses by apical flagellin/TLR5 interaction ex vivo and does not require access to the basolateral membrane as postulated in cell culture models.
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PMID:The ex vivo response of human intestinal mucosa to enteropathogenic Escherichia coli infection. 1913 13

The potentially probiotic strain Lactobacillus plantarum BFE 1685 isolated from a child's faeces and the probiotic strain Lactobacillus rhamnosus GG were investigated for their capability to influence the innate immune response of HT29 intestinal epithelial cells towards Salmonella enterica serovar Typhimurium. Furthermore, their capacity to modulate toll-like receptor expression of HT29 cells was investigated at the mRNA and protein levels. TNF-alpha was used in cell culture with HT29 cells to mimic an inflammatory background, and in the presence of this chemokine HT29 cells were sensitised to respond to the Lactobacillus strains as evidenced by an increased response in IL-8 production. In addition, when HT29 cells were first treated with lactobacilli and then infected with S. Typhimurium, the IL-8 levels in response to S. Typhimurium were significantly higher, indicating that HT29 cells were sensitised by lactobacilli. Neither of the lactobacilli was able to stimulate TLR4 production at the mRNA level, however, TLR2 and TLR9 transcription levels measured by quantitative PCR were up-regulated when HT29 cells were incubated with lactobacilli, but not with S. Typhimurium. Up-regulation of TLR9 expression was higher for L. rhamnosus GG than for L. plantarum BFE 1685. Expression levels of TLR2 and TLR5 were enhanced also at the protein level as determined by flow cytometry after staining with the respective antibodies. In contrast, TLR9 expression was not significantly up-regulated, which may be explained by protein degradation, or possible down-stream regulatory effects. These findings show that stimulation of specific signaling pathways occurs in the cross-talk between probiotic bacteria and gut epithelium cells, which can help to explain the adjuvant properties of probiotic lactobacilli.
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PMID:Lactobacilli stimulate the innate immune response and modulate the TLR expression of HT29 intestinal epithelial cells in vitro. 1952 7

Flagellin acting via TLR5 (Toll-like receptor 5) is a key regulator of the host response to the gut microbial flora in both health and disease. The present study has investigated regulation of flagellin-TLR5 signalling in human colonocytes (HT29-19A) by IFNgamma (interferon-gamma), a cytokine released early in the inflammatory process which has multiple effects on gut epithelial function that may facilitate abnormal responses to enteric bacteria. Flagellin induced a dose-dependent secretion of chemokines CXCL8 and CCL2 in the human colonocyte line, HT29-19A. Exposure to IFNgamma did not induce chemokine secretion, but markedly potentiated responses to flagellin, increasing CXL8 gene expression and protein secretion by approx. 4-fold. Potentiation by IFNgamma was independent of changes in TLR5 and was associated with a rapid, sustained increase in expression of the downstream adaptor molecule MyD88 (myeloid differentiation factor 88). Knockdown of MyD88 expression using siRNA (small interfering RNA) abolished flagellin-dependent CXCL8 secretion and the potentiating effect of IFNgamma. Exposure of non-transformed mouse and human colonocytes to IFNgamma also increased MyD88 expression. STAT (signal transducer and activator of transcription) 1 knockdown and use of the broad-spectrum JAK (Janus kinase)-STAT inhibitor AG490 had no effect on IFNgamma-mediated up-regulation of MyD88. The findings of the present study suggest that IFNgamma sensitizes colonic epithelial cells to bacterial flagellin via a largely STAT-independent up-regulation of MyD88 expression leading to increased secretion of immunomodulatory factors. These results indicate that epithelial responses to flagellin are potentiated by IFNgamma, most likely mediated by increased MyD88 expression. The present study adds to our understanding of the spectrum of effects of this cytokine on gut epithelium that may contribute to bacterial-driven inflammation in the gut.
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PMID:Potentiation of flagellin responses in gut epithelial cells by interferon-gamma is associated with STAT-independent regulation of MyD88 expression. 1961 29

Salmonella enterica serovar Typhimurium and Campylobacter jejuni are major human pathogens, yet colonise chickens without causing pathology. The aim of this study was to compare intestinal innate immune responses to both bacterial species, in a 4-week-old broiler chicken model. Challenged and control birds were sacrificed and tissue samples taken for histopathology and RNA extraction. No significant clinical or pathological changes were observed in response to infection with either bacterial species. Expression of selected genes involved in pathogen detection and the innate immune response were profiled in caecal tissues by quantitative real-time PCR. TLR4 and TLR21 gene expression was transiently increased in response to both bacterial species (P<0.05). Significant increases in TLR5 and TLR15 gene expression were detected in response to S. Typhimurium but not to C. jejuni. Transient increases of proinflammatory cytokine (IL6 and IFNG) and chemokine (IL8 and K60) genes increased as early as 6h in response to S. Typhimurium. Minimal cytokine gene expression was detected in response to C. jejuni after 20h. IL8 gene expression however, was significantly increased by 24-fold (P<0.01). The differential expression profiles of innate immune genes in both infection models shed light on the tailored responses of the host immune system to specific microbes. It is further evidence that innate regulation of these responses is an important prerequisite to preventing development of disease.
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PMID:Innate immune gene expression differentiates the early avian intestinal response between Salmonella and Campylobacter. 1963 28

Toll-like receptors (TLRs) are increasingly implicated in the pathogenesis of cancer. The present study describes TLR expression and function in healthy and malignant airway epithelial cells. The squamous cell carcinoma cell line Detroit-562 was compared with the healthy bronchial epithelial cell line NL-20 and primary human nasal epithelial cells (HNECs). TLR2, TLR3 and TLR5 were present in primary head and neck squamous cell carcinomas (HNSCCs). Consistent with this, Detroit-562 expressed TLR2, TLR3 and TLR5, whereas NL-20 expressed mainly TLR3 and HNECs expressed TLR2-5. In Detroit-562, Pam(3)CSK(4), poly(I:C) and flagellin, ligands for TLR2, TLR3 and TLR5, respectively, induced an up-regulation of intercellular adhesion molecule 1 (ICAM-1), an increase in interleukin (IL)-6 and IL-8 secretion and a decrease in cell viability. Additionally, poly(I:C) affected IL-1beta production and the migratory behaviour of Detroit-562. NL-20 responded with a slight increase in IL-8 secretion upon poly(I:C) stimulation. Poly(I:C) induced a small increase in IL-1beta, IL-6 and IL-8 production in HNECs, while Pam(3)CSK(4) increased viability. The TLR signalling was transcription-dependent, but the pathways involved differed among TLRs as well as cells. In Detroit-562, TLR2 and TLR5 activation was mediated via c-jun N-terminal kinase (JNK)-, p38-, phosphatidylinositol 3-kinase (PI3K)- and nuclear factor (NF)-kappaB-related pathways, while TLR3 was dependent on NF-kappaB. In NL-20, TLR3 signalled via p38, and in HNECs, NF-kappaB, JNK and extracellular signal-regulated kinase (ERK) appeared to be involved. We found that TLR agonists induced a robust response in HNSCCs, characterized by generation of inflammation and cell death. A similar response was not seen in normal epithelial cells. Thus, the TLR system should be considered an important target in future antitumour immunotherapy.
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PMID:Toll-like receptor agonists induce inflammation and cell death in a model of head and neck squamous cell carcinomas. 1974 Mar 21

In mammals, Toll-like receptors (TLRs) are the principal family of innate immune pattern recognition receptors (PRRs). The main function for TLRs is the detection of molecular patterns associated with invading pathogens. We investigated TLR expression and function in three established human endometrial epithelial cell lines, including hTERT-EEC, HEC-1B and Ishikawa cells, and clarified the application of these endometrial cell lines as in vitro models for studying TLR expression and function in the female reproductive tract. TLR gene expression was examined by RT-PCR and protein localization by immunohistochemistry. Our results showed that TLR expression in these cell lines is comparable to published literature on TLR expression in primary human endometrial tissue. TLR function was investigated by the detection of IL-6 and IL-8 production by ELISA in response to TLR2, TLR3, TLR5, TLR7 and TLR9 ligands. We found that hTERT-EEC cells were responsive to TLR5 ligand and HEC-1B cells respond to TLR3 and TLR5 ligands. In contrast, Ishikawa cells respond only to PMA/I which was used as a positive control for IL-8 production. Finally, we investigated the influence of flagellin as a TLR5 stimulant on TLR5 expression in these cell lines by QPCR. Our results showed that the endometrial cell lines showed a tendency for increased TLR5 expression in response to flagellin stimulation and in hTERT-EEC cells this tendency was statistically significant. These results suggest that hTERT-EEC, HEC-1B and Ishikawa cell lines can be used as in vitro models to investigate innate immune responses of endometrial cells in the female reproductive tract.
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PMID:Expression and function of Toll-like receptors in human endometrial epithelial cell lines. 1995 41

Keratinocytes in the skin play an important role in innate immune responses by secreting chemokines. This study aimed to determine if keratinocyte cell lines can be used for studies of innate immune mechanisms. Human primary keratinocytes and the HaCaT, CCD 1106 KERTr (KERTr) and HEK001 cell lines were treated with a panel of Toll-like receptor (TLR)-ligands. Expression of IL-8, CCL20, CXCL9 and CXCL10 was determined. All three cell lines expressed TLR1-6 and TLR9. KERTr cells responded to the same TLR-ligands as primary keratinocytes. Overall HEK001 responded similarly, but appeared to be relatively more sensitive to flagellin. This was in agreement with increased expression of TLR5. The expression profiles were most distinct in HaCaT cells. Furthermore, our data confirm and extend previously reported TLR7 and TLR8 independent IL-8 secretion by keratinocytes after Imiquimod treatment. The different cell lines represent complementary tools for molecular studies of innate immunity of the skin.
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PMID:Chemokine expression by human keratinocyte cell lines after activation of Toll-like receptors. 2010 Jan 99

Flagellin contains conserved N/C domains for TLR5 binding to activate innate immunity and a middle hypervariable domain harboring the major antigenic epitopes. However, conflict results existed in the previous studies as to whether the hypervariable domain was involved in the cytokine production and adjuvancy of flagellin. Here we constructed three flagellin variants (designated as FliCDelta190-278, FliCDelta220-320, and FliCDelta180-400) with deletions in the hypervariable domain. Our data demonstrated that all deletion variants lost substantial antigenicity but not mucosal adjuvancy. Surprisingly, the variant with deletion of amino acids 220-320 (FliCDelta220-320) induced higher production of IL-8, MCP-1, and TNF-alpha, and showed higher mucosal adjuvancy than full-length FliC flagellin. Our data supported the notion that the hypervariable domain was involved in the cytokine production by flagellin and more importantly demonstrated that the hypervariable domain was important for the mucosal adjuvancy of flagellin.
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PMID:Recombinant flagellins with partial deletions of the hypervariable domain lose antigenicity but not mucosal adjuvancy. 2010 2


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