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)

Topical immunosuppressant therapy is widely used in the treatment of inflammatory skin diseases such as psoriasis and atopic dermatitis. Besides its beneficial therapeutic effects, application of topical anti-inflammatory drugs may render the epidermis more vulnerable to invading pathogens by suppressing innate immune responses in keratinocytes, such as cytokine production and Toll-like receptor (TLR) expression. In order to evaluate and compare the immunosuppressive effects of different immunosuppressant drugs on keratinocytes, we treated lipopolysaccharide (LPS)-stimulated and -unstimulated normal human keratinocytes with the synthetic corticosteroid budesonide and the macrolide tacrolimus. The expressions of the pattern recognition receptors (PRRs) TLR2 and TLR4 were measured by quantitative RT-PCR, pro-inflammatory cytokines IL-1alpha, IL-8 and TNF-alpha were monitored by quantitative RT-PCR and by ELISA, and alterations in TLR2 protein level were measured by flow cytometry. Budesonide had a suppressive effect on both constitutive and LPS-induced IL-8 gene expression. The amount of TNF-alpha mRNA was diminished in unstimulated keratinocytes, while TLR2 mRNA expression was markedly enhanced both in unstimulated and LPS-treated cells after incubation with budesonide. This increase in TLR2 mRNA expression was also detectable at the protein level in LPS-stimulated cells. Tacrolimus had no effect on any of the examined genes. Budesonide, but not tacrolimus, significantly inhibited the NF-kappaB-dependent luciferase reporter activity in HaCaT cells after induction with LPS or TNF-alpha. Although tacrolimus and budesonide are both effective treatments in some inflammatory skin diseases, the data provided here imply differences in local therapeutic and adverse effects of these two topical immunosuppressants.
 ...
PMID:Budesonide, but not tacrolimus, affects the immune functions of normal human keratinocytes. 1642 71

Lipoproteins from gram-positive and -negative bacteria, mycoplasma, and shorter synthetic lipopeptide analogues activate cells of the innate immune system via the Toll-like receptor TLR2/TLR1 or TLR2/TLR6 heterodimers. For this reason, these compounds constitute highly active adjuvants for vaccines either admixed or covalently linked. The lanthionine scaffold has structural similarity with the S-(2,3-dihydroxypropyl)cysteine core structure of the lipopeptides. Therefore, lanthionine-based lipopeptide amides were synthesized and probed for activity as potential TLR2 agonists or antagonists. A collection of analytically defined lipolanthionine peptide amides exhibited an inhibitory effect of the TLR2-mediated IL-8 secretion when applied in high molar excess to the agonistic synthetic lipopeptide Pam3Cys-Ser-(Lys)4-OH. Structure-activity relationships revealed the influence of the chirality of the two alpha-carbon atoms, the chain lengths of the attached fatty acids and fatty amines, and the oxidation level of the sulfur atom on the inhibitory activity of the lipolanthionine peptide amides.
 ...
PMID:Lipolanthionine peptides act as inhibitors of TLR2-mediated IL-8 secretion. Synthesis and structure-activity relationships. 1650 90

In the course of screening inhibitors of matrix metalloproteinase (MMP)-9 induction in macrophages, we isolated decursin, a coumarin compound, from the roots of Angelicae gigas. As a marker for the screening and isolation, we tested expression of MMP-9 in RAW264.7 cells and THP-1 cells after treatment with bacterial lipopolysaccharide (LPS), the TLR-4 ligand. Decursin suppressed MMP-9 expression in cells stimulated by LPS in a dose-dependent manner at concentrations below 60 microM with no sign of cytotoxicity. The suppressive effect of decursin was observed not only in cells stimulated with ligands for TLR4, TLR2, TLR3, and TLR9 but also in cells stimulated with interleukin (IL)-1beta, and tumor necrosis factor (TNF)-alpha, indicating that the molecular target of decursin is common signaling molecules induced by these stimulants. In addition to the suppression of MMP-9 expression, decursin blocked nitric oxide production and cytokine (IL-8, MCP-1, IL-1beta, and TNF-alpha) secretion induced by LPS. To find out the molecular mechanism responsible for the suppressive effect of decursin, we analyzed signaling molecules involved in the TLR-mediated activation of MMP-9 and cytokines. Decursin blocked phosphorylation of IkappaB and nuclear translocation of NF-kappaB in THP-1 cells activated with LPS. Furthermore, expression of a luciferase reporter gene under the promoter containing NF-kappaB binding sites was blocked by decursin. These data indicate that decursin is a novel inhibitor of NF-kappaB activation in signaling induced by TLR ligands and cytokines.
 ...
PMID:Decursin inhibits induction of inflammatory mediators by blocking nuclear factor-kappaB activation in macrophages. 1651 May 59

The objective of the present study was to examine the expression of Toll-like receptors (TLRs) by mouse uterine epithelial cells and to determine if stimulation of the expressed TLR induces changes in cytokine and/or chemokine secretion. Using RT-PCR, the expression of TLRs 1-6 by mouse uterine epithelial cells was demonstrated, with TLRs 7-9 expressed only periodically. In the absence of pathogen-associated molecular patterns, polarized uterine epithelial cells constitutively secrete interleukin (IL) 1A, cysteine-cysteine ligand (CCL) 2, IL6, granulocyte-macrophage colony-stimulating factor 2 (CSF2), tumor necrosis factor A (TNFA), CSF3, and IL8 in vitro, with levels of cytokines/chemokines secreted into the apical compartment being significantly greater than those released into the basolateral compartment. When added to the apical surface for 48 h before analysis, the TLR2-agonist Pam3Cys-Ser-(Lys)4 and TLR1/6-agonist peptidoglycan increased epithelial cell apical secretion of IL1A, CCL2, and IL6 and apical/basolateral bidirectional secretion of CSF2, TNFA, CSF3, and IL8 when compared to controls. The TLR3-agonist poly (I:C) significantly increased bidirectional secretion of CCL2, IL6, TNFA, and CSF2 and basolateral secretion of CSF3. Lastly, the TLR4-agonist lipopolysaccharide increased bidirectional secretion CCL2, CSF2, TNFA, CSF3, and IL8 and apical secretion of IL6. These results indicate that mRNAs for Tlr1 through Tlr6 are expressed by uterine epithelial cells and that treatment with specific TLR agonists alters the expression of key chemokines and proinflammatory cytokines that contribute to the defense of the uterus against potential pathogens.
 ...
PMID:Expression of Toll-like receptors (TLR) and responsiveness to TLR agonists by polarized mouse uterine epithelial cells in culture. 1651 Aug 38

Bruton's tyrosine kinase (Btk), the gene mutated in the human immunodeficiency X-linked agammaglobulinemia, is activated by LPS and is required for LPS-induced TNF production. In this study, we have investigated the role of Btk both in signaling via another TLR (TLR2) and in the production of other proinflammatory cytokines such as IL-1beta, IL-6, and IL-8. Our data show that in X-linked agammaglobulinemia PBMCs, stimulation with TLR4 (LPS) or TLR2 (N-palmitoyl-S-[2, 3-bis(palmitoyloxy)-(2R)-propyl]-(R)-cysteine) ligands produces significantly less TNF and IL-1beta than in normal controls. In contrast, a lack of Btk has no impact on the production of IL-6, IL-8, or the anti-inflammatory cytokine, IL-10. Our previous data suggested that Btk lies within a p38-dependent pathway that stabilizes TNF mRNA. Accordingly, TaqMan quantitative PCR analysis of actinomycin D time courses presented in this work shows that overexpression of Btk is able to stabilize TNF, but not IL-6 mRNA. Furthermore, using the p38 inhibitor SB203580, we show that the TLR4-induced production of TNF, but not IL-6, requires the activity of p38 MAPK. These data provide evidence for a common requirement for Btk in TLR2- and TLR4-mediated induction of two important proinflammatory cytokines, TNF and IL-1beta, and reveal important differences in the TLR-mediated signals required for the production of IL-6, IL-8, and IL-10.
 ...
PMID:Bruton's tyrosine kinase is required for TLR2 and TLR4-induced TNF, but not IL-6, production. 1651 32

Francisella tularensis is a virulent Gram-negative intracellular pathogen. To address the signaling routes involved in the response of host cells to LPS from F. tularensis live vaccine strain (LVS), experiments were performed in transiently transfected 293 cells. Induction of kappaB-driven transcriptional activity by 2.5 mug ml(-1) F. tularensis LPS isolated by phenol-water and ether-water extraction, was observed in cells transfected with Toll-like receptor (TLR) 4 and MD-2, although CD14 was required for optimal induction. Conversely, TLR2, TLR2/TLR1 or TLR2/TLR6 transfected cells did not show kappaB-driven transcriptional activity in the presence of F. tularensis LPS. In human monocytic cells, F. tularensis LPS activated extracellular signal-regulated kinases and the production of pro-inflammatory proteins. Concentrations of 5-10 mug ml(-1) F. tularensis LPS elicited a similar pattern of mRNA and protein induction than 0.1 mug ml(-1) E. coli LPS, including the expression of CXC chemokines (IL-8, Gro and IFN-gamma-inducible protein-10); CC chemokines (monocyte chemoattractant protein-1 and -2, macrophage-derived chemoattractant, macrophage inflammatory protein-1alpha and -1beta and RANTES (regulated upon activation, normal T cell expressed and secreted) and pro-inflammatory cytokines (IL-6 and tumor necrosis factor alpha). Altogether, these data indicate that LPS from F. tularensis LVS signals via TLR4 at higher concentrations than those required for E. coli LPS, which may explain the inflammatory reaction and the low endotoxic response associated to vaccination with LVS in humans.
 ...
PMID:Francisella tularensis LPS induces the production of cytokines in human monocytes and signals via Toll-like receptor 4 with much lower potency than E. coli LPS. 1657 69

Gram-positive bacterial products such as peptidoglycan (PGN) and lipoteichoic acid (LTA) are potent stimulators of innate inflammatory responses. We previously reported that lipopolysaccharide (LPS), a major biologically active agent of gram-negative bacteria, induces a proinflammatory response via the Toll-like receptor (TLR) 4 in hepatic stellate cells (HSCs). Here we investigated the mechanism of proinflammatory action by PGN and LTA in activated human HSCs. Following treatment with either TNF-alpha or IL-1beta, expression of TLR2 and CD14 was determined by real-time PCR and Western blotting. NF-kappaB activation was assessed by NF-kappaB-driven luciferase assay and electrophoretic mobility shift assay. Interleukin-8 (IL-8) from culture supernatant was measured by ELISA. Activated human HSCs express TLR2 and CD14, which are receptors for PGN and LTA signaling. TNF-alpha and IL-1beta significantly upregulated the expression of TLR2 mRNA and protein in HSCs. PGN and LTA induced NF-kappaB activation and stimulated production of IL-8 in HSCs. Pretreatment with TNF-alpha or IL-1beta augmented NF-kappaB activation and IL-8 production in response to PGN or LTA. Both PGN- and LTA-induced NF-kappaB activation and IL-8 secretion were completely inhibited by anti-TLR2 blocking antibody (T2.5). These findings suggest that TNF-alpha or IL-1beta primed HSCs enhance the production of IL-8 in response to PGN and LTA through augmentation of the TLR2 system.
 ...
PMID:Hepatic stellate cells primed with cytokines upregulate inflammation in response to peptidoglycan or lipoteichoic acid. 1661 4

Dendritic cells (DC) have a central role in the initiation of adequate immune responses. They recognize pathogens by means of Toll-like receptors (TLR) and link innate to adaptive immune responses by releasing proinflammatory cytokines and inducing T cell proliferation. We conducted this study to evaluate the expression and function of TLR on human lung DC subsets and to study their T cell stimulatory capacity. TLR gene expression by human pulmonary DC was evaluated by RT-PCR, while protein expression was analyzed by flow cytometry. We investigated cytokine release by DC in response to different TLR ligands. T cell stimulatory capacity was evaluated by mixed leukocyte reactions of purified lung DC with allogeneic T cells. Myeloid dendritic cells type 1 (mDC1) and myeloid dendritic cells type 2 (mDC2) express mRNA transcripts for TLR1, TLR2, TLR3, TLR4, TLR6, and TLR8. Flow cytometric analysis demonstrated high TLR2 protein expression for mDC1 and moderate TLR4 expression for mDC2. mDC1 and mDC2 release proinflammatory cytokines (TNF-alpha, IL-1beta, IL-6, and IL-8) in response to TLR2 and TLR4 ligands. TLR3 ligands induce cytokine release in mDC1, but not in mDC2. Plasmacytoid DC (pDC) express TLR7 and TLR9 and release proinflammatory cytokines in response to imiquimod and IFN-alpha in response to CpG oligonucleotides. mDC1 are strong inducers of T cell proliferation, while pDC hardly induce any T cell proliferation. mDC2 have an intermediate T cell-stimulatory capacity. Our results show divergent roles for the different human lung DC subsets, both in innate and adaptive immune responses.
 ...
PMID:Different roles for human lung dendritic cell subsets in pulmonary immune defense mechanisms. 1662 25

Alloiococcus otitidis has been found to be associated with otitis media with effusion. In this study we investigated whether TLR2 and collectins, surfactant protein A (SP-A) and mannose-binding lectin (MBL), interacted with A. otitidis. Both SP-A and MBL bound to A. otitidis in a Ca(2+)-dependent manner. A. otitidis induced IL-8 secretion from U937 cells and NF-kappaB activation in TLR2-transfected HEK293 cells. However, the cells transfected with the mutant TLR2(P681H) did not respond to A. otitidis. In addition, A. otitidis co-sedimented a recombinant soluble form of the extracellular TLR2 domain, indicating direct binding of the bacterium to TLR2. SP-A and MBL augmented the phagocytosis of A. otitidis by J774A.1 cells. The collectin-stimulated phagocytosis of A. otitidis was significantly attenuated when fucoidan and polyinosinic acid were co-incubated. Immunoblotting analysis revealed that MBL was present in the middle ear effusion from patients with otitis media. These results demonstrate that A. otitidis is a ligand for the collectins and TLR2, and that the collectins enhance the phagocytosis of A. otitidis by macrophages, suggesting important roles of the collectins and TLR2 in the innate immunity of the middle ear against A. otitidis infection.
 ...
PMID:Alloiococcus otitidis is a ligand for collectins and Toll-like receptor 2, and its phagocytosis is enhanced by collectins. 1670 1

More than 90% of all publications on endotoxin were carried out with endotoxins (lipopolysaccharide, LPS) from enterobacteriaceae. We compared the immune stimulatory potency of 11 different LPSs using human whole blood incubations. While the majority of LPSs induced cytokine release equipotently, a 1,000-fold more LPS from Pseudomonas aeruginosa or Vibrio cholerae was still less potent in inducing TNF, IL-1 beta, IL-10 and IFN-gamma though it potently induced nanogram quantities IL-8. All LPSs tested, regardless of the micro-organism, showed Toll-like receptor (TLR)4-dependence, except for the LPSs from P. aeruginosa and V. cholerae, which were both TLR4- and TLR2-dependent. Interestingly, UV-inactivated P. aeruginosa bacteria, although Gram-negative, also showed TLR2- and TLR4-dependence. Re-purification of commercial LPS preparations by phenol re-extraction led to a complete loss of the TLR2 dependency, indicating contamination with lipoproteins. In the Limulus amebocyte lysate assay, often performed to exclude contamination in purified water likely to originate from P. aeruginosa, P. aeruginosa LPS was only 2-fold less potent than LPS from S. abortus equi or the assay standard LPS from E. coli. This results in an overestimation of pyrogenic burden by a factor of 500 in the sample when compared with the biological activity of highly purified P. aeruginosa LPS in human whole blood.
 ...
PMID:Endotoxin evaluation of eleven lipopolysaccharides by whole blood assay does not always correlate with Limulus amebocyte lysate assay. 1671 88


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>