Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lipopolysaccharide (LPS) engages Toll-like receptor 4 (TLR4) on various cells to initiate inflammatory and angiogenic pathways. FADD is an adaptor protein involved in death receptor-mediated apoptosis. Here we report a role for FADD in regulation of TLR4 signals in endothelial cells. FADD specifically attenuates LPS-induced activation of c-Jun NH(2)-terminal kinase and phosphatidylinositol 3'-kinase in a death domain-dependent manner. In contrast, FADD-null cells show hyperactivation of these kinases. Examining physical associations of endogenous proteins, we show that FADD interacts with interleukin-1 receptor-associated kinase 1 (IRAK1) and MyD88. LPS stimulation increases IRAK1-FADD interaction and recruitment of the IRAK1-FADD complex to activated MyD88. IRAK1 is required for FADD-MyD88 interaction, as FADD does not associate with MyD88 in IRAK1-null cells. By shuttling FADD to MyD88, IRAK1 provides a mechanism for controlled and limited activation of the TLR4 signaling pathway. Functionally, enforced FADD expression inhibited LPS- but not vascular endothelial growth factor-induced endothelial cell sprouting, while FADD deficiency led to enhanced production of proinflammatory cytokines induced by stimulation of TLR4 and TLR2, but not TLR3. Reconstitution of FADD reversed the enhanced production of proinflammatory cytokines. Thus, FADD is a physiological negative regulator of IRAK1/MyD88-dependent responses in innate immune signaling.
Mol Cell Biol 2007 Nov
PMID:FADD negatively regulates lipopolysaccharide signaling by impairing interleukin-1 receptor-associated kinase 1-MyD88 interaction. 1778 32

Bordetella pertussis causes a profound inflammatory response in lungs of infected individuals. The adenylate cyclase toxin (ACT) of B. pertussis is a potent enzyme that converts cytosolic ATP into cAMP, and is required for virulence in vivo. During infection, secreted ACT binds to macrophages utilizing the beta2 integrin, Mac-1 (CR3, CD11b/CD18), and subsequent intoxication by ACT inhibits essential antibacterial activities of macrophages. Additionally, Mac-1 has been reported to be a co-receptor for TLR4 required for the full induction of some LPS-responsive genes, including pro-inflammatory cyclooxygenase 2 (COX-2). We have examined the effect of ACT on COX-2 expression in HEK293T cells expressing Mac-1 and in murine macrophages. We report that ACT induces COX-2 in a manner that absolutely requires the catalytic activity of this enzyme and Mac-1 expression dramatically enhanced the sensitivity of cells to ACT-dependent COX-2 induction. The mechanism of COX-2 induction by ACT utilizes the cAMP-PKA-CREB-dependent pathway. Finally, ACT and TLR2 or TLR4 act synergistically to increase COX-2 expression. These data suggest that ACT contributes significantly to the inflammatory response induced by B. pertussis infection by augmenting COX-2 expression and provides evidence against the concept that ACT functions exclusively via its inhibitory effects on phagocytic leucocytes.
Mol Microbiol 2007 Nov
PMID:Bordetella pertussis adenylate cyclase toxin (ACT) induces cyclooxygenase-2 (COX-2) in murine macrophages and is facilitated by ACT interaction with CD11b/CD18 (Mac-1). 1792 97

M-Ficolin is a member of the ficolin family of proteins, which is expressed by monocytes. We have determined the expression of this gene in various populations of this lineage in man and found lower levels of M-Ficolin mRNA in the more mature CD14(+)CD16(+) monocytes as compared to the classical CD14(++) monocytes. Monocyte-derived macrophages generated by in vitro culture for 5 days strongly reduced M-Ficolin mRNA and protein. Mature tissue macrophages from the lung and from breast milk also showed a very low level of M-Ficolin transcripts. When cells of the monocytic cell line Mono Mac 6 cell were treated with TLR2 and TLR4 ligands for 24 h then there was an average of 6- and 9-fold induction of the M-Ficolin mRNA, respectively. After 72 h induction was in average 30- and 80-fold for TLR2 and TLR4 stimulation, respectively. Treatment of monocyte-derived macrophages for 3 days with TLR4 ligand gave an average 4-fold induction and alveolar macrophages treated with TLR4 ligand showed a 12-fold induction. These data show that M-Ficolin expression is silenced in macrophages but can be re-activated after prolonged activation via TLRs.
Mol Immunol 2008 Mar
PMID:Expression of M-Ficolin in human monocytes and macrophages. 1792 56

Staphylococcus aureus, but not E. coli pathogens frequently cause subclinical, chronic infections of the mammary gland. We examined here, if inadequate activation of the bovine TLR2 and TLR4 pathogen receptors by ligands derived from S. aureus pathogens might contribute to molecular mechanisms underpinning the escape strategies from mammary immune defence of this pathogen. We show that infections with live E. coli, but not S. aureus pathogens induce strongly IL-8 and TNFalpha gene expression in the udders. Yet, preparations of heat-killed bacteria from both pathogens activate equally well bovine TLR2 and TLR4 receptors to induce NF-kappaB activation, as shown in the HEK293 reconstitution system of TLR-signal transduction. LTA prepared from the S. aureus strain used to infect the cows activates the bovine TLR2 as strongly as the entire, heat-killed pathogen. Both pathogens induce in primary bovine mammary epithelial cells (pbMEC) IL-8 and TNFalpha gene expression, but S. aureus to less than 5% of the degree caused by E. coli. This impaired proinflammatory activation is paralleled by a complete lack of NF-kappaB activation in pbMEC by S. aureus or LTA. In contrast, E. coli and LPS activate strongly NF-kappaB in these cells. A large proportion of this activation is attributable to TLR-mediated signalling, since a dual transdominant negative DN-MyD88-DN-TRIF factor blocks >80% of the pathogen-related NF-kappaB activation in pbMEC. Our results prove that impaired binding of TLR-ligands from the pathogenic S. aureus strain are not the cause for the inadequate mammary immune response elicited by this pathogen. Rather, the pathogen causing subclinical mastitis impairs NF-kappaB activation in MEC thereby severely weakening the immune response in the udder.
Mol Immunol 2008 Mar
PMID:Bovine TLR2 and TLR4 properly transduce signals from Staphylococcus aureus and E. coli, but S. aureus fails to both activate NF-kappaB in mammary epithelial cells and to quickly induce TNFalpha and interleukin-8 (CXCL8) expression in the udder. 1793 7

We isolated cDNA encoding porcine MyD88 (poMyD88) from Peyer's patches (Pps) of GALT. The complete open reading frame (ORF) of poMyD88 contains 879 bp encoding a deduced 293 aa residues. The amino acid sequence of poMyD88 was characterized by N-terminal death, intermediate and C-terminal Toll/IL-1 receptor (TIR) domains. The putative poMyD88 protein shares a higher level of homology with its human (87.2% amino acid identity) than with its mouse (77.4% amino acid identity) counterpart. Overexpression of poMyD88 participated in the further enhanced activation of NF-kappaB in human embryonic kidney (HEK) 293 cells expressing porcine TLR2 and porcine TLR4/MD-2, but not porcine RP105/MD-1 after stimulation with the corresponding ligands. The expression levels of MyD88 were highest in the spleen and mesenteric lymph nodes (MLNs), and lower in digestive tissues of newborn swine. In adult swine, the expression levels in the digestive tissues were lower than those in MLNs and the spleen. These results suggest that an MyD88-dependent signaling pathway is present in newborn as well as in adult swine and that it is involved in the innate immune system of these animals.
Cell Mol Immunol 2007 Oct
PMID:Molecular cloning and functional characterization of porcine MyD88 essential for TLR signaling. 1797 17

Toll-like receptors (TLRs) mediate inflammation in sepsis, but their role in sepsis-induced respiratory failure is unknown. Hypoxic pulmonary vasoconstriction (HPV) is a unique vasoconstrictor response that diverts blood flow away from poorly ventilated lung regions. HPV is impaired in sepsis and after challenge with the TLR4 agonist lipopolysaccharide (LPS). Unlike TLR4 agonists, which are present only in Gram-negative bacteria, TLR2 agonists are ubiquitously expressed in all of the major classes of microorganisms that cause sepsis, including both Gram-positive and Gram-negative bacteria and fungi. We tested the hypothesis that (S)-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-N-palmitoyl-(R)-Cys-(S)-Ser(S)-Lys(4)-OH, trihydrochloride (Pam3Cys), a TLR2 agonist, impairs HPV and compared selected pulmonary and systemic effects of Pam3Cys vs. LPS. HPV was assessed 22 h after challenge with saline, Pam3Cys, or LPS by measuring the increase in the pulmonary vascular resistance of the left lung before and during left lung alveolar hypoxia produced by left mainstem bronchus occlusion (LMBO). Additional endpoints included arterial blood gases during LMBO, hemodynamic parameters, weight loss, temperature, physical appearance, and several markers of lung inflammation. Compared with saline, challenge with Pam3Cys caused profound impairment of HPV, reduced systemic arterial oxygenation during LMBO, weight loss, leukopenia, and lung inflammation. In addition to these effects, LPS-challenged mice had lower rectal temperatures, metabolic acidosis, and were more ill appearing than Pam3Cys-challenged mice. These data indicate that TLR2 activation impairs HPV and induces deleterious systemic effects in mice and suggest that TLR2 pathways may be important in sepsis-induced respiratory failure.
Am J Physiol Lung Cell Mol Physiol 2008 Feb
PMID:Activation of Toll-like receptor 2 impairs hypoxic pulmonary vasoconstriction in mice. 1805 42

MUC1 (MUC1 in humans and Muc1 in nonhuman species) is a transmembrane mucin-like glycoprotein expressed in epithelial cells lining various mucosal surfaces as well as hematopoietic cells. Recently, we showed that Muc1(-/-) mice exhibited greater inflammatory responses to Pseudomonas aeruginosa or its flagellin compared with their wild-type littermates, and our studies with cultured cells revealed that MUC1/Muc1 suppressed the Toll-like receptor (TLR) 5 signaling pathway, suggesting its anti-inflammatory role. Here we demonstrate that other TLR signaling (TLR2, 3, 4, 7, and 9) is also suppressed by MUC1/Muc1. The results from this study suggest that MUC1/Muc1 may play a crucial role during airway infection and inflammation by various pathogenic bacteria and viruses.
Am J Respir Cell Mol Biol 2008 Mar
PMID:MUC1 mucin is a negative regulator of toll-like receptor signaling. 1807 92

G-protein coupled receptor kinases (GRKs) and arrestins (ARRs) are ubiquitously distributed crucial signaling proteins that are critical in the regulation of responsiveness of G-protein coupled receptors (GPCRs). Toll-like receptors (TLRs) (class of pattern recognition receptors) play a vital role in macrophage biology and innate immunity. Because GPCR responsiveness is regulated in part by the expression levels of GRKs/ARRs, the focus of this work was to uncover potential cross-talk mechanisms between TLRs and GPCRs via regulation of GRK/ARR expression in primary mouse macrophages. We demonstrate here that activation of TLR2 and 4 (but not TLR3 and 7) significantly decrease ARR2 but not ARR3 protein levels in macrophages. Compared to this, activation of TLR2, 4, and 7 (but not TLR3) significantly decrease GRK5 and 6 protein levels. Surprisingly, GRK2 protein levels are markedly increased by TLR2, 3, 4 and 7. Mechanistically, expression of ARR2 and GRK5 are regulated at transcriptional as well as post-translational levels. Downregulation of GRK6 by LPS is regulated primarily at the post-translational level. TLR4-induced GRK2 level, however, is both transcriptionally and post-transcriptionally regulated. Our results demonstrate previously unknown crucial regulatory mechanisms that alter ARR/GRK expression levels in macrophages that might modify many, if not all, GPCR-mediated innate immune responses.
Mol Immunol 2008 Apr
PMID:Toll-like receptors differentially regulate GPCR kinases and arrestins in primary macrophages. 1818 38

We have recently demonstrated that oxidants can activate monocytes via an action on Toll-like receptor (TLR) 2; however, it is unclear what functional consequence this has on immune surveillance for Gram-negative and -positive bacteria. Gram-negative and -positive bacteria and their related pathogen-associated molecular patterns (PAMPs) are sensed by TLR4 and TLR2, respectively. In the current study, we used a human monocyte cell line to show that oxidants prime cells to subsequent challenge with Gram-negative or -positive bacteria as well as PAMPs specific for TLR4 (LPS), TLR2/1 (Pam(3)CSK4), TLR2/6 (FSL-1), Nod1 (FK565), and Nod2 (MDP Lys 18). Similarly, activation of TLR4 with LPS primed for subsequent activation of cells by agonists of the TLR2/6 or TLR2/1 complex. However, no synergy was noted when cells were costimulated with Pam(3)CSK4 and FSL-1. We then tested blood (and isolated monocytes) derived from healthy smokers, which is oxidant primed, making it more sensitive to bacterial or PAMP stimulation when compared with blood of nonsmokers. Thus an oxidant stimulation, possibly via an action on TLR2 or associated transduction pathways, provides a signal that initiates inflammatory responses and sensitizes cells to pathogenic insults.
Mol Med
PMID:Gram-positive and Gram-negative bacteria synergize with oxidants to release CXCL8 from innate immune cells. 1823 74

Gangliosides, sialic acid-containing glycosphingolipids, are implicated in many neuronal diseases, but the precise molecular mechanisms underlying their pathological activities are poorly understood. Here we report that TLR2 participates in the initiation of ganglioside-triggered inflammatory signaling responses. Using FACS analysis and immunofluorescence microscopy, we found that gangliosides rapidly enhanced the cell surface expression of TLR2 in microglia, while reducing that of TLR4. The ganglioside-dependent increase of TLR2 expression was also observed at the messenger and protein levels. We also showed that gangliosides stimulate the interaction of TLR2 with Myd88, an adaptor for TLRs, and obtained evidence that lipid raft formation is closely associated with the ganglioside-induced activation of TLR2 and subsequent inflammatory signaling. These results collectively suggest that TLR2 contributes to the ability of gangliosides to cause inflammatory conditions in the brain.
Mol Cells 2008 Feb 29
PMID:Contribution of TLR2 to the initiation of ganglioside-triggered inflammatory signaling. 1831 20


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