Search results for LY96

Showing 17 results out of 40

×

Species

Types

Compartments

Reaction types

Search properties

Species

Types

Compartments

Reaction types

Search properties

Protein (3 results from a total of 3)

Identifier: R-HSA-9707658
Species: Homo sapiens
Compartment: extracellular region
Primary external reference: UniProt: LY96: Q9Y6Y9
Identifier: R-HSA-2201307
Species: Homo sapiens
Compartment: endosome membrane
Primary external reference: UniProt: Q9Y6Y9
Identifier: R-HSA-166047
Species: Homo sapiens
Compartment: plasma membrane
Primary external reference: UniProt: LY96: Q9Y6Y9

Reaction (6 results from a total of 14)

Identifier: R-HSA-9707594
Species: Homo sapiens
Compartment: extracellular region
Secreted LY96 (MD-2) is a large protein that confers lipopolysaccharide (LPS) sensitivity to Toll-like receptor 4 (TLR4). Hemes can bind to secreted LY96 at a different site than LPS, resulting in comparable TLR4 activation (Belcher et al, 2002; Visintin et al, 2001).
Identifier: R-HSA-5432825
Species: Homo sapiens
Compartment: extracellular region, plasma membrane
High mobility group box protein 1 (HMGB1) is an endogenous molecule that upon stress can be released into the extracellular milieu (Andersson U et al. 2000; Scaffidi P et al. 2002; Bonaldi T et al. 2003; Chen G et al. 2004; Bell CW et al. 2006; Beyer C et al. 2012; Yang H et al. 2013).

Using surface plasmon resonance (SPR) analysis recombinant HMGB1 was shown to bind TLR4:LY96(MD2) in a concentration-dependent manner (Yang H et al. 2010; Yang H et al. 2015). The binding required cysteine at the position 106 whereas the C106A HMGB1 mutant failed to bind TLR4:LY96 (Yang H et al. 2010). In addition, C106A and C106S HMGB1 failed to stimulate TNF release in mouse peritoneal macrophages (Yang H et al. 2010). The activity of HMGB1 was found to depend on the redox state of three cysteines at positions 23, 45 and 106 (C23, C45 and C106) (Urbonaviciute V et al. 2009; Venereau E et al. 2012, 2013; Yang H et al. 2012, 2013). Tandem mass spectrometric analysis revealed that the inflammatory activities of HMGB1 required both the formation of an intramolecular disulfide bond between C23 and C45 and the reduced state of C106 (thiol state, C106-SH) (Yang H et al. 2012; Venereau E et al. 2012). Both terminal oxidation of these cysteines to sulfonates (CySO3-) with reactive oxygen species (ROS) and their complete reduction to thiols (CySH) abrogated the cytokine-stimulating activity of HMGB1 in cultured human primary macrophages and mouse macrophage-like RAW 264.7 cells (Yang H et al. 2012; Venereau E et al. 2012). Biosensor-based SPR analysis confirmed that only the disulfide bond (C23-S-S-C45)-containing HMGB1 binds to LY96 (MD2) with high affinity (apparent Kd = 12 nM) regardless of whether LY96 or HMGB1 was immobilized on the sensor chip (Yang H et al. 2015). Moreover, TLR4 and LY96 (MD2) were recruited into CD14-containing lipid rafts of mouse RAW264.7 macrophages after stimulation with HMGB1, suggesting that an optimal HMGB1-dependent TLR4 activation in vitro required the co-receptor CD14 (Kim S et al. 2013). In addition to stimulating cells by direct interaction with innate immune receptors, HMGB1 was found to form immunostimulatory complexes with cytokines and other endogenous and exogenous ligands such as bacterial lipopolysaccharide (LPS) (Youn JH et al. 2008; Wahamaa H et al. 2011; Hreggvidsdottir HS et al. 2009) HMGB1 in complex with LPS, IL1alpha or IL1beta boosted proinflammatory cytokine- and matrix metalloproteinase (MMP3) production in synovial fibroblasts obtained from rheumatoid arthritis (RA) and osteoarthritis (OA) patients (Wahamaa H et al. 2011; He ZW et al. 2013). HMGB1 was reported to associate and amplify the activity of LPS (TLR4 ligand), CpG-ODN (TLR9 ligand) or Pam3CSK4 (TLR1:TLR2 ligand) in a synergistic manner when added to the cultures of human peripheral blood mononuclear cell (PBMC) (Hreggvidsdottir HS et al. 2009).

Identifier: R-HSA-6805943
Species: Homo sapiens
Compartment: extracellular region, plasma membrane
The human event of S100A1 is inferred from the mouse data.

S100A1 is a Ca(2+)-sensing protein of the EF-hand family. S100A1 is expressed predominantly in cardiomyocytes, where it regulates Ca(2+)-dependent signaling events (Wright NT et al. 2005; Cannon BR et al. 2011; Brinks H et al. 2011; Yu J et al. 2015; Rohde D et al. 2014; Ritterhoff J & Most P 2012). In response to ischemic/hypoxic damage of cardiomyocytes, S100A1 is released or transferred to the extracellular region through open channels on membrane (Rohde D et al. 2014). The extracellular S100A1 activates signal and promotes cell survival pathways, including inflammation response via Toll-like receptor 4 (TLR4) (Brinks H et al. 2011; Yu J et al. 2015; Rohde D et al. 2014). In rodent H9C2 cells S100A1 was found to regulate the inflammatory response and oxidative stress via TLR4/ROS/NFkappaB pathway ( Yu J et al. 2015).

Identifier: R-HSA-2201293
Species: Homo sapiens
Compartment: endosome membrane, plasma membrane
Upon LPS stimulation TLR4 is internalized into endosomes where the signaling pathway is triggered through the adaptors TRAM and TRIF leading to the activation of IRF3 and induction of IFN-beta [Tanimuro N et al 2008; Kagan JC et al 2008]. While TLR4 translocation to endosomes is governed by known regulators of general endocytic processes such as dynamins and clathrin, other proteins that specifically regulate LPS-stimulated TLR4 endocytosis have been also identified [Husebye et al 2006; Kagan JC et al 2008; Zanoni I et al 2011]. Thus, CD14 has been implicated both in transporting LPS to TLR4 and in delivering TLR4 to an endosomal compartment. TLR4 translocation activated by CD14 appears to be Syk-mediated, and requires its downstream effector phospholipase C gamma 2 (PLCgamma2), which in turn induces a drop in the concentration of PIP2 required for endosomal sealing [Zanoni I et al 2011]. It has also been shown that PLCgamma2 induces inositol 1,4,5-trisphosphate (IP(3)) production and subsequent calcium (Ca2+) release. Released intracellular Ca2+ was reported to mediate TLR4 trafficking and subsequent activation of IRF3. [Aki D et al 2008; Chiang CY et al 2012].
Identifier: R-HSA-5432849
Species: Homo sapiens
Compartment: extracellular region, plasma membrane
S100A8 (also known as MRP8) and S100A9 (MRP14) are Ca(2+)-binding proteins that are associated with acute and chronic inflammation and cancer (Ehrchen JM et al. 2009; De Jong HK et al. 2015). S100A8 & S100A9 have been identified as important damage-associated molecular patterns (DAMPs) recognized by TLR4 (Foell D et al. 2007; Vogl t et al. 2007; 2012; Kang JH et al. 2015). Surface plasmon resonance studies showed that S100A8 can directly interact with TLR4:MD2 complex with Kd of 1.1-2.5 x 10e-8 M ((Vogl T et al. 2007). Human embryonic kidney cells stably transfected with TLR4,CD14 and MD2 demonstrated a strong induction of proinflammatory cytokines like TNFalpha and IL8 after stimulation with LPS as well as with S100A8 (Vogl T et al. 2007). Induction of NFkB responses by S100A9 in human monocytic THP-1 cell line and mouse bone marrow-derived dendritic cells was TLR4-dependent (Riva M et al. 2012). Moreover, induction of MUC5AC mRNA and protein in normal human bronchial epithelial cells as well as NCI-H292 lung carcinoma cells occurred in a dose-dependent manner trough TLR4 signaling pathway (Kang JH et al. 2015). In addition, S100A8:S100A9 was reported to regulate cell survival of human neutrophils through a signaling mechanism involving an activation of MEK:ERK1 via TLR4 (Atallah M et al. 2012). In experimental mouse models the proinflammatory and TLR4-dependent activities of S100A8:S100AA9 were further confirmed (Vogl t et al. 2007; Loser K et al. 2010; Kuipers MT et al. 2013; Deguchi A et al. 2015).

S100A8 & S100A9 are constitutively expressed in neutrophils, myeloid-derived dendritic cells, platelets, osteoclasts and hypertrophic chondrocytes (Hessian PA et al. 1993; Kumar A et al. 2003; Healy AM et al. 2006; Schelbergen RF et al 2012). In contrast, these molecules are induced under inflammatory stimuli in monocytes/macrophages, microvascular endothelial cells, keratinocytes and fibroblasts (Hessian PA et al. 1993; Eckert RL et al. 2004; Viemann D et al. 2005; McCormick MM et al. 2005; Hsu K et al. 2005). S100A8 & S100A9 tend to form homodimers and heterodimers (Kumar RK et al. 2001; Riva M et al. 2013; Korndorfer IP et al. 2007). The heterodimeric S100A8:S100A9 complex is termed calprotectin and is considered as the predominantly occurring form. In response to stress S100A8:S100A9 is primarily released from activated or necrotic neutrophils to extracellular milieu where it functions as an innate immune mediator of infection, autoimmunity, and cancer (Ehrchen JM et al. 2009; Rammes A et al. 1997; Frosch M et al. 2000; Loser K et al. 2010).

S100A8 and S100A9 protein levels were elevated in patients with a wide range of inflammatory diseases, including rheumatoid arthritis, juvenile idiopathic arthritis, inflammatory bowel disease, acute lung inflammation, sepsis and vasculitis (Ehrchen JM et al. 2009; van Zoelen MA et al. 2009; Vogl T et a;. 2012; Holzinger D et al. 2012; Rahman MT et al. 2014; Anink J et al. 2015. Increased S100A8 and S100A9 serum levels have been also identified as independent risk predictors for various cardiovascular diseases such as acute coronary syndrome and myocardial infarction (Yonekawa K et al. 2011; Cotoi OS et al. 2014; Larsen SB et al. 2015).

Identifier: R-HSA-5432852
Species: Homo sapiens
Compartment: extracellular region, plasma membrane
The hydrophilic pulmonary surfactant proteins SP-A (SFTPA) and SP-D (SFTPD) belong to the C-type lectin family. Members of the C-type lectin family contain an N-terminal collagen-like domain and a C-terminal carbohydrate recognition domain (CRD) (Kishore U et al. 2006). The CRD allows binding to various components, including carbohydrates, phospholipids or charge patterns found on microbes, allergens and dying cells, while the collagen region can interact with receptor molecules present on immune cells in order to initiate clearance mechanisms (Kishore U et al. 2006). SP-A and SP-D are known to bind to a range of microbial pathogens that invade the lungs (Eggleton P & Reid KB 1999; Crouch E & Wright JR 2001; McCormack FX1 & Whitsett JA 2002; Nayak A et al. 2012; Jakel A et al. 2013). SP-A and SP-D form large oligomeric structures to orchestrate the pulmonary innate immune defense by mechanisms that may involve binding and agglutinating pathogens (Kuan SF et al 1992; Griese M & Starosta V 2005; Yamada C et al. 2006; Kishore U et al. 2006; Zhang L et al. 2001). The direct interaction of SP-A with macrophages was shown to promote phagocytosis of Klebsiella pneumoniae, Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa (Van Iwaarden JF et al. 1994; Hickman-Davis JM et al. 2002; Ding J et al. 2004; Mikerov AN et al. 2008; Gil M et al. 2009).

SP-A and SP-D were found to bind to the recombinant soluble form of extracellular TLR4 domain (sTLR4) and MD2 in a Ca2+ -dependent manner, with involvement of the CRD region (Yamada et al. 2006; Yamazoe M et al. 2008). SP-A was also shown to interact with CD14 (Sano H. et al. 1999). Studies involving gene knock-out mice, murine models of lung hypersensitivity and infection together with functional characterization of cell surface receptors revealed both pro- and anti-inflammatory functions of SP-A and SP-D in the control of lung inflammation in mammals (Guillot L et al. 2002; Madan T et al. 2001, 2005, 2010; Wang JY & Reid KB 2007; Yamada et al. 2006; Yamazoe M et al. 2008; Wang G et al. 2010). Anti-inflammatory effects of SP-A caused inhibition of NF-kB activation and accumulation of inhibitory protein I kappa B-alpha (IkB-alpha) in LPS-challenged alveolar macrophages (AM) (Wu Y et al. 2004). SP-A also inhibited tumor necrosis factor-alpha (TNFalpha) expression induced by smooth LPS but not by rough LPS in the human macrophage-like cell line U937 cells (Sano H. et al. 1999). In addition, SP-A attenuated cell surface binding of smooth LPS and subsequent NF-kB activation in TLR4/MD2 expressing human embryonic kidney (HEK293) cells (Yamada et al. 2006). Like SP-A, SP-D bound to complex of sTLR4:MD2 was found to down regulate a secretion of TNFalpha and activation of NF-kB in LPS-stimulated AM and TLR4/MD-2-transfected HEK293 cells (Yamazoe M et al. 2008). SP-A and SP-D are thought to prevent LPS-elicited inflammatory responses by altering LPS binding to its receptors, TLR4:MD2 or CD14 (Sano H. et al. 1999; Yamada et al. 2006; Yamazoe M et al. 2008).

Complex (6 results from a total of 21)

Identifier: R-HSA-166050
Species: Homo sapiens
Compartment: plasma membrane
Identifier: R-HSA-2201291
Species: Homo sapiens
Compartment: endosome membrane
Identifier: R-HSA-166172
Species: Homo sapiens
Compartment: endosome membrane
Identifier: R-HSA-2559578
Species: Homo sapiens
Compartment: endosome membrane
Identifier: R-HSA-166850
Species: Homo sapiens
Compartment: plasma membrane
Identifier: R-HSA-8870679
Species: Homo sapiens
Compartment: plasma membrane

Set (1 results from a total of 1)

Identifier: R-HSA-9708724
Species: Homo sapiens
Compartment: plasma membrane

Icon (1 results from a total of 1)

Species: Homo sapiens
TLR4 cooperates with LY96 and CD14 to mediate the innate immune response to bacterial lipopolysaccharide (LPS)
Cite Us!