Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Host response to injury and infection is accompanied by a rapid rise in the blood of acute-phase proteins such as serum amyloid A (SAA). Although SAA has been used as a marker for inflammatory diseases, its role in the modulation of inflammation and immunity has not been defined. Human neutrophils respond to SAA with secretion of the proinflammatory cytokines interleukin 8 (IL-8) and, to a lesser extent, tumor necrosis factor alpha (TNF-alpha). The induction of IL-8 secretion by SAA involves both transcription and translation and correlates with activation of nuclear factor kappaB (NF-kappaB). The proximal signaling events induced by SAA include mobilization of intracellular Ca(2+) and activation of the mitogen-activated protein kinases ERK1/2 and p38, both required for the induced IL-8 secretion. Pertussis toxin effectively blocks SAA-induced IL-8 secretion indicating involvement of a Gi-coupled receptor. Overexpression of FPRL1/LXA4R in HeLa cells results in a significant increase of the expression of NF-kappaB and IL-8 luciferase reporters by SAA, and an antibody against the N-terminal domain of FPRL1/LXA4R inhibits IL-8 secretion. Lipoxin A4, which binds to FPRL1/LXA4R specifically, decreases SAA-induced IL-8 secretion significantly. Collectively, these results indicate that the cytokine-like property of SAA is manifested through activation of the Gi-coupled FPRL1/LXA4R, which has been known to mediate the anti-inflammatory effects of lipoxin A4. The ability of FPRL1/LXA4R to mediate 2 drastically different and opposite functions suggests that it plays a role in the modulation of inflammatory and immune responses.
 ...
PMID:Serum amyloid A induces IL-8 secretion through a G protein-coupled receptor, FPRL1/LXA4R. 1239 91

The integrity of lipid microdomains is disrupted after cell treatment with cholesterol-depleting reagents, such as methyl-beta-cyclodextrin (MCD). We investigated the roles of lipid microdomains in the regulation of intracellular signaling events and functional responses in isolated human neutrophils. Treatment of neutrophils with MCD caused inhibition of intracellular calcium increase evoked by interleukin-8 (IL-8) or low concentrations of formyl-Met-Leu-Phe (fMLP). No significant decrease of the initial peak of the calcium response was measured when neutrophils were stimulated with 100 nM or higher concentrations of fMLP. MCD inhibited the phosphorylation of extracellular signal-regulated kinase (Erk) induced by IL-8 or lower concentrations of fMLP. However, Erk phosphorylation evoked by higher concentrations of fMLP was only slightly affected. MCD treatment increased phosphorylation of p38 MAP kinase and caused strong up-regulation of both CD11b and CD66b in resting neutrophils. Cholesterol depletion greatly inhibited IL-8-induced elastase release but had little effect of fMLP-induced degranulation. Our study brings evidence suggesting that lipid microdomains are critically required for the signaling events triggered by IL-8. Calcium mobilization and elastase release induced by WKYMVM, a selective agonist for formyl peptide receptor-like 1 (FPRL1), were significantly inhibited by MCD, suggesting that the resistance of fMLP-mediated responses to MCD is not related to the partition of receptor subtypes to lipid microdomains. It is more probable that cholesterol depletion interferes with the ability of different G proteins to couple to their corresponding receptors and this might account for the differential effects of MCD treatment on chemoattractant-induced effects in human neutrophils.
 ...
PMID:Membrane lipid microdomains differentially regulate intracellular signaling events in human neutrophils. 1642 87

Neutrophil chemotaxis has been shown to be regulated by two different signalling pathways that allow strong chemoattractants, such as bacterial-derived formylated peptides, to dominate over endogenous attractants, such as interleukin-8 (IL-8). Here we show that triggering of the formyl peptide receptor (FPR) with f-Met-Leu-Phe (fMLF) substantially reduced the neutrophil superoxide production induced by activation of the CXC receptors with IL-8. When the order of agonists was reversed, the cells were primed in their response to fMLF, suggesting that the signalling hierarchy between strong, so-called end-type (i.e. fMLF) and weak or intermediate-type (i.e. IL-8) chemoattractants, is also operating during activation of the NADPH-oxidase. The same result was obtained when fMLF was replaced with the hexapeptide, WKYMVM, specific for the formyl peptide-like receptor 1 (FPRL1). There were additional differences between the agonist receptor pairs fMLF/FPR, WKYMVM/FPRL1 and IL-8/CXCR. In contrast to FPR and FPRL1, no reserve pool of CXCR was present in subcellular granules and it was impossible to prime the oxidative response transduced through CXCR by the addition of priming agents such as tumour necrosis factor-alpha and platelet-activating factor. Moreover, the cytoskeleton-disrupting substance, cytochalasin B, had no effect either on IL-8-triggered oxidase activation or on CXCR reactivation. A pertussis toxin-sensitive G-protein is involved in signalling mediated through both FPR and CXCR, and the signalling cascades include a transient intracellular calcium increase, as well as downstream p38 MAPK and phosphoinositide 3-kinase activation. The data presented in this study provide support for two different signalling pathways to the neutrophil NADPH-oxidase, used by ligand binding to FPR/FPRL1 or CXCR, respectively.
 ...
PMID:The mechanism for activation of the neutrophil NADPH-oxidase by the peptides formyl-Met-Leu-Phe and Trp-Lys-Tyr-Met-Val-Met differs from that for interleukin-8. 1514 63

Many mammalian antimicrobial peptides (AMPs) have multiple effects on antimicrobial immunity. We found that temporin A (TA), a representative frog-derived AMP, induced the migration of human monocytes, neutrophils, and macrophages with a bell-shaped response curve in a pertussis toxin-sensitive manner, activated p44/42 MAPK, and stimulated Ca(2+) flux in monocytes, suggesting that TA is capable of chemoattracting phagocytic leukocytes by the use of a G(ialpha) protein-coupled receptor. TA-induced Ca(2+) flux in monocytes was cross-desensitized by an agonistic ligand MMK-1 specific for formyl peptide receptor-like 1 (FPRL1) and vice versa, suggesting that TA uses FPRL1 as a receptor. This conclusion was confirmed by data showing that TA selectively stimulated chemotaxis of HEK 293 cells transfected with human FPRL1 or its mouse ortholog, murine formyl peptide receptor 2. In addition, TA elicited the infiltration of neutrophils and monocytes into the injection site of mice, indicating that TA is also functionally chemotactic in vivo. Examination of two additional temporins revealed that Rana-6 was also able to attract human phagocytes using FPRL1, but temporin 1P selectively induced the migration of neutrophils using a distinct receptor. Comparison of the chemotactic and antimicrobial activities of several synthetic analogues suggested that these activities are likely to rely on different structural characteristics. Overall, the results demonstrate that certain frog-derived temporins have the capacity to chemoattract phagocytes by the use of human FPRL1 (or its orthologs in other species), providing the first evidence suggesting the potential participation of certain amphibian antimicrobial peptides in host antimicrobial immunity.
 ...
PMID:Temporin A and related frog antimicrobial peptides use formyl peptide receptor-like 1 as a receptor to chemoattract phagocytes. 1529 82

Resveratrol (3,5,4'-trihydroxystilbene) (RV) is a constituent of grape seeds with anti-inflammatory and anti-oxidant activities. In this study, we examined the capacity of RV to modulate the function of G protein-coupled chemoattractant receptors, which play important roles in inflammation and immune responses. RV, over a non-cytotoxic concentration range, inhibited chemotactic and calcium mobilization responses of phagocytic cells to selected chemoattractants. At low micromolar concentrations, RV potently reduced superoxide anion production by phagocytic leukocytes in response to the bacterial chemotactic peptide fMLF, a high affinity ligand for formylpeptide receptor FPR, and A beta42, an Alzheimer's disease-associated peptide and a ligand for the FPR variant FPRL1. In addition, RV reduced phosphorylation of extracellular signal-regulated kinase (ERK1/2) and the activation of nuclear factor NF-kappaB induced by formylpeptide receptor agonists. These results suggest that the inhibition of the function of chemoattractant receptors may contribute to the anti-inflammatory properties of RV. Thus, RV may be therapeutically promising for diseases in which activation of formylpeptide receptors contributes to the pathogenic processes.
 ...
PMID:The grape component resveratrol interferes with the function of chemoattractant receptors on phagocytic leukocytes. 1621 21

Urokinase-type plasminogen activator (uPA) binding to uPAR induces migration, adhesion, and proliferation through multiple interactions with G proteins-coupled receptor FPRL1, integrins, or the epidermal growth factor (EGF) receptor (EGFR). At least two forms of uPAR are present on the cell surface: full-length and cleaved uPAR, each specifically interacting with one or more transmembrane proteins. The connection between these interactions and the effects on the signaling pathways activation is not clear. We have exploited an uPAR mutant (hcr, human cleavage resistant) to dissect the pathways involved in uPA-induced cell migration. This mutant is not cleaved by proteases, is glycosylphosphatidylinositol anchored, and binds uPA with a normal K(d). Both wild-type (wt) and hcr-uPAR are able to mediate uPA-induced migration, are constitutively associated with the EGFR, and associate with alpha3beta1 integrin upon uPA binding. However, they engage different pathways in response to uPA. wt-uPAR requires both integrins and FPRL1 to mediate uPA-induced migration, and association of wt-uPAR to alpha3beta1 results in uPAR cleavage and extracellular signal-regulated kinase (ERK) activation. On the contrary, hcr-uPAR does not activate ERK and does not engage FPRL1 or any other G protein-coupled receptor, but it activates an alternative pathway initiated by the formation of a triple complex (uPAR-alpha3beta1-EGFR) and resulting in the autotyrosine phosphorylation of EGFR.
 ...
PMID:An uncleavable uPAR mutant allows dissection of signaling pathways in uPA-dependent cell migration. 1626 71

The human G-protein-coupled formyl peptide receptor-like 1 (FPRL1) and its mouse homologue mFPR2 mediate the chemotactic activity of a variety of polypeptides associated with inflammation and bacterial infection, including the 42-amino acid form of amyloid beta peptide (Abeta42), a pathogenic factor in Alzheimer disease. Because mFPR2 was inducible in mouse microglial cells by proinflammatory stimulants, such as bacterial lipopolysaccharide, a ligand for the Toll-like receptor 4 (TLR4), we investigated the role of TLR2 in the regulation of mFPR2. We found that a TLR2 agonist, peptidoglycan (PGN) derived from Gram-positive bacterium Staphylococcus aureus, induced considerable mFpr2 mRNA expression in a mouse microglial cell line and primary microglial cells. This was associated with a markedly increased chemotaxis of the cells in response to mFPR2 agonist peptides. In addition, activation of TLR2 markedly enhanced mFPR2-mediated uptake of Abeta42 by microglia. Studies of the mechanistic basis showed that PGN activates MAPK and IkappaBalpha, and the effect of PGN on induction of mFPR2 was dependent on signaling pathways via ERK1/2 and p38 MAPKs. The use of TLR2 on microglial cells by PGN was supported by the fact that N9 cells transfected with short interfering RNA targeting mouse TLR2 failed to show increased expression of functional mFPR2 after stimulation with PGN. Our results demonstrated a potentially important role for TLR2 in microglial cells of promoting cell responses to chemoattractants produced in lesions of inflammatory and neurodegenerative diseases in the brain.
 ...
PMID:Activation of Toll-like receptor 2 on microglia promotes cell uptake of Alzheimer disease-associated amyloid beta peptide. 1633 65

Although the level of serum amyloid A has been reported to be up-regulated during inflammatory response, the role of serum amyloid A on the regulation of inflammation and immune response has not been elucidated. We found that serum amyloid A stimulated the production of tumor necrosis factor (TNF)-alpha and interleukin (IL)-10, which are proinflammatory and anti-inflammatory cytokines, respectively, in human monocytes. Low concentrations of serum amyloid A stimulated TNF-alpha production with maximal activity at 6 h after stimulation, whereas high concentrations of serum amyloid A stimulated IL-10 production with maximal activity at 12 h. The activations of the two cytokines by serum amyloid A occurred at both the transcription and translational levels. Signaling events induced by serum amyloid A included the activation of two mitogen-activated protein kinases (extracellular signal-regulated kinase and p38 kinase), which were found to be required for TNF-alpha and IL-10 production, respectively. The stimulation of formyl peptide receptor-like-1-expressing RBL-2H3 cells, but not of vector-expressing RBL-2H3 cells with serum amyloid A, induced mitogen-activated protein kinases activation and the accumulation of the RNAs of these two cytokines. Together, our findings suggest that serum amyloid A modulates contrary immune responses via formyl peptide receptor-like 1, by inducing TNF-alpha or IL-10, and demonstrate that extracellular signal-regulated kinase and p38 kinase play counteracting roles in this process.
 ...
PMID:Serum amyloid A induces contrary immune responses via formyl peptide receptor-like 1 in human monocytes. 1656 9

Human formyl peptide receptor (FPR)-like 1 (FPRL1) and its mouse homologue mFPR2 are functional receptors for a variety of exogenous and host-derived chemotactic peptides, including amyloid beta 1-42 (Abeta(42)), a pathogenic factor in Alzheimer's disease. Because mFPR2 in microglial cells is regulated by proinflammatory stimulants including TLR agonists, in this study we investigated the capacity of IFN-gamma and the CD40 ligand (CD40L) to affect the expression and function of mFPR2. We found that IFN-gamma, when used alone, induced mFPR2 mRNA expression in a mouse microglial cell line and primary microglial cells in association with increased cell migration in response to mFPR2 agonists, including Abeta(42). IFN-gamma also increased the endocytosis of Abeta(42) by microglial cells via mFPR2. The effect of IFN-gamma on mFPR2 expression in microglial cells was dependent on activation of MAPK and IkappaB-alpha. IFN-gamma additionally increased the expression of CD40 by microglial cells and soluble CD40L significantly promoted cell responses to IFN-gamma during a 6-h incubation period by enhancing the activation of MAPK and IkappaB-alpha signaling pathways. We additionally found that the effect of IFN-gamma and its synergy with CD40L on mFPR2 expression in microglia was mediated in part by TNF-alpha. Our results suggest that IFN-gamma and CD40L, two host-derived factors with increased concentrations in inflammatory central nervous system diseases, may profoundly affect microglial cell responses in the pathogenic process in which mFPR2 agonist peptides are elevated.
 ...
PMID:Induction of the formyl peptide receptor 2 in microglia by IFN-gamma and synergy with CD40 ligand. 1723 25

The N-formyl peptide receptor-like 1 (FPRL1) is a G protein-coupled receptor (GPCR) that transmits intracellular signals in response to a variety of agonists, many of them being clearly implicated in human pathology. beta-arrestins are adaptor proteins that uncouple GPCRs from G protein and regulate receptor internalization. They can also function as signal transducers through the scaffolding of signaling molecules, such as components of the extracellular signal-regulated kinase (ERK) cascade. We investigated the role of beta-arrestins in ligand-induced FPRL1 internalization and signaling. In HEK293 cells expressing FPRL1, fluorescence microscopy revealed that agonist-stimulated FPRL1 remained co-localized with beta-arrestins during endocytosis. Internalization of FPRL1, expressed in a mouse embryonic fibroblast (MEF) cell line lacking endogenous beta-arrestins, was highly compromised. This distinguishes FPRL1 from the prototypical formyl peptide receptor FPR that is efficiently internalized in the absence of beta-arrestins. In both HEK293 and MEF cells, FPRL1-mediated ERK1/2 activation was a rapid and transient event. The kinetics and extent of ERK1/2 activation were not significantly modified by beta-arrestin overexpression. The pattern of FPRL1-mediated ERK1/2 activation was similar whether cells express or not beta-arrestins. Furthermore, treatment of the FPRL1 expressing cells with pertussis toxin inhibited ERK1/2 activation in MEF and in HEK293 cells. These results led us to conclude that activation of ERK1/2 mediated by FPRL1 occurs primarily through G protein signaling. Since beta-arrestin-mediated signaling has been observed essentially for receptors coupled to G proteins other than G(i), this may be a characteristic of G(i) protein-coupled chemoattractant receptors.
 ...
PMID:The role of beta-arrestins in the formyl peptide receptor-like 1 internalization and signaling. 1759 11


1 2 3 Next >>