Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic smoking is characterized by immunosuppressive changes in the airways, leading to chronic colonization with bacteria, which in turn may contribute to the chronic obstructive pulmonary disease. The mechanisms causing this immunosuppression, however, are poorly characterized. This study evaluated whether cigarette smoke can inhibit endotoxin (LPS)-induced inflammatory cytokine production in bronchial epithelial cells and, if so, what the mechanisms are behind this effect. Pretreatment with cigarette smoke extract (CSE) concentration dependently inhibited the LPS-induced GM-CSF and IL-8 protein release, which was accompanied by decreased expression of mRNA in human bronchial epithelial cells (Beas-2B). The increase of neutrophil chemotaxis induced by conditioned medium from LPS-treated Beas-2B cells was also suppressed by CSE. In addition, the activity of LPS-induced transcription factor AP-1, but not NF-kappaB, was down-regulated by CSE. Notably, at the concentrations used, CSE had no effect on number or viability of Beas-2B cells. These data indicate that cigarette smoke possesses immunosuppressive properties by down-regulating the bacterial pathogen-induced neutrophil-mobilizing cytokine production via suppression of AP-1 activation in the airways. Hence, this study suggests a novel mechanism by which cigarette smoke may contribute to chronic colonization and chronic obstructive pulmonary disease in smokers.
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PMID:Cigarette smoke inhibits lipopolysaccharide-induced production of inflammatory cytokines by suppressing the activation of activator protein-1 in bronchial epithelial cells. 1535 67

We have identified a novel signaling pathway that leads to expression of matrix metalloproteinase-9 (MMP-9) in murine macrophages in response to the bacterial endotoxin, LPS. We showed that p38 kinase was essential for this induction and observed that LPS-induced MMP-9 expression was sensitive to rottlerin, a putative protein kinase Cdelta (PKCdelta) inhibitor. However neither infection with a retrovirus expressing a dominant negative mutant of PKCdelta nor down-regulation of PKCdelta by prolonged PMA treatment affected MMP-9 expression, thus excluding involvement of PKCdelta. Interestingly, LPS-induced MMP-9 expression and p38 kinase phosphorylation were shown to be suppressed by the antioxidant N-acetylcysteine and the flavoenzyme inhibitor diphenyleneiodonium chloride, but not by pyrrolidine dithiocarbamate, an NF-kappaB inhibitor. In addition, LPS was found to induce the production of mitochondrial reactive oxygen species (ROS) and this effect was rottlerin-sensitive, suggesting an inhibitory effect of rottlerin on mitochondrial ROS. LPS-induced MMP-9 expression and p38 kinase phosphorylation were also inhibited by rotenone, a specific inhibitor of mitochondrial complex I, supporting the role of mitochondrial ROS in LPS signaling to MMP-9. Finally, we showed that the ROS-p38 kinase cascade targets the transcription factor AP-1. Taken together, our findings identify a ROS-p38 kinase-AP-1 cascade as a novel pathway mediating LPS signaling to MMP-9 expression in macrophages.
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PMID:Lipopolysaccharide induces matrix metalloproteinase-9 expression via a mitochondrial reactive oxygen species-p38 kinase-activator protein-1 pathway in Raw 264.7 cells. 1555 94

Francisella tularensis is a highly virulent intracellular pathogen responsible for tularemia. This bacterium is capable of infecting many mammalian species and various cell types, but little is known about the mechanisms of survival and interactions with host cells. We examined the number of infected host cells, cytotoxicity and the role of apoptosis or necrosis in infection-induced cell death. Our results demonstrate that F. tularensis LVS induces apoptosis of infected macrophages within 10 h. At later time points we were also able to detect a dramatic increase in the proportion of necrotic macrophages. We investigated the signalling pathways involved in infection-induced cell death by analysing three mitogen-activated protein kinase (MAPK) pathways that are known to be activated by LPS stimulation; p42/p44 MAPK (Erk1/2), transcription factor c-Jun and p38 MAPK. We identified post-translational activation of both p42 MAPK and p44 MAPK by phosphorylation at threonine and tyrosine residues after infection. Furthermore, treatment of infected cells with MEK1/2 inhibitors abrogated phosphorylation of p42/p44 MAPK and inhibited macrophage apoptosis and necrosis after infection. In contrast, phosphorylation and kinase activity of p38 MAPK was significantly lower in F. tularensis-infected cells, and inhibition of p38 MAPK activity induced apoptosis in uninfected cells. When we monitored JNK-dependent phosphorylation of the transcription factor c-Jun, we did not observe any reactivity with either SAPK/JNK or phospho-SAPK/JNK antibodies at any time point. In conclusion, we demonstrate that F. tularensis LVS infection induces macrophage apoptosis. This process requires activation of the p42/p44 MAPK pathway and is associated with reduced p38 MAPK activity, indicating that infection-induced cell death can be caused by perturbation of these two signalling pathways.
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PMID:The role of MAPK signal pathways during Francisella tularensis LVS infection-induced apoptosis in murine macrophages. 1582 Jan 49

Rheumatoid arthritis (RA) causes a symmetric, inflammatory polyarthritis that results in joint destruction and significant disability. Signaling pathways that regulate the production of cytokines and destructive enzymes have been implicated in its pathogenesis and represent potential therapeutic targets. The IkappaB kinase (IKK)-related kinase, IKKepsilon/IKKi, which plays a pivotal role in regulating antiviral gene transcription, is constitutively expressed by cultured fibroblast-like synoviocytes (FLS) and could participate in the pathogenesis of RA. In the current studies we demonstrate that IKKepsilon protein is expressed in RA and osteoarthritis synovium and that the protein is found primarily in the synovial intimal lining. Functional studies in cultured FLS showed that IKKepsilon kinase activity is rapidly induced by cytokines, although IkappaB phosphorylation is significantly less compared with IKK2. Because NF-kappaB activation is similar in wild-type and IKKepsilon knockout murine FLS, studies were performed to identify an alternative substrate for IKKepsilon. Interestingly, c-Jun is a more efficient substrate for IKKepsilon immunocomplexes in human FLS and this activity appears to be independent of JNK. The functional relevance of IKKepsilon was examined using murine IKKepsilon(-/-) cultured FLS. IL-1-, TNF-alpha-, and LPS-mediated induction of matrix metalloproteinases, MMP3 and MMP13, is significantly decreased in the IKKepsilon(-/-) cells. These data suggest a novel role for the IKKepsilon complex in synovial inflammation, extracellular matrix destruction, and activation of the viral program and innate immune response in RA.
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PMID:Regulation of c-Jun phosphorylation by the I kappa B kinase-epsilon complex in fibroblast-like synoviocytes. 1587 44

Monocytic cells constitute an important defense mechanism against invading pathogens by recognizing conserved pathogens components. The recognition leads to activation of intracellular pathways involving nuclear factor kappa B (NF-kappaB) and mitogen-activated protein kinases (MAPK), such as the c-Jun NH2-terminal kinase (JNK), and p38. We show that in vitro infection with Francisella tularensis results in activation of NF-kappaB, phosphorylation of p38 and c-Jun, and secretion of TNF-alpha in adherent mouse peritoneal cells, in the mouse macrophage-like cell line J774A.1, in the human macrophage cell line THP-1, and in human peripheral blood monocytic cells. This occurred after infection with the human live vaccine strain, F. tularensis LVS or a mutant strain denoted deltaiglC, which lacks expression of a 23-kDa protein, or after addition of killed F. tularensis LVS. Addition of purified F. tularensis LPS resulted in no discernible effects on the cells. When the effects were followed up to 5 h, activation persisted in cultures with killed bacteria or infected with the deltaiglC strain. In contrast, the signal transduction activation and secretion of TNF-alpha were down-regulated within the 5h period in mouse peritoneal cells, J774 cells or human peripheral blood mononuclear cells infected with F. tularensis LVS. Together, the results suggest that infection with live F. tularensis LVS bacteria leads to a rapid induction of a proinflammatory response in mouse and human cells but after internalization of bacteria, this response is completely or partly down-regulated in most cell types. This down-regulation does not occur when cells are infected with the mutant deltaiglC.
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PMID:Francisella tularensis LVS initially activates but subsequently down-regulates intracellular signaling and cytokine secretion in mouse monocytic and human peripheral blood mononuclear cells. 1592 73

The heterophil is the major polymorphonuclear cell in birds with a functional capacity akin to that of the mammalian neutrophil. Herein, we demonstrate that heterophils constitutively express TLR1/6/10, TLR2 type 1, TLR2 type 2, TLR3, TLR4, TLR5, and TLR7 mRNA. Furthermore, TLR agonists, including flagellin (from Salmonella typhimurium, FGN), peptidoglycan (from Staphylococcus aureus, PGN), ultra-pure lipopolysaccharide (from Salmonella minnesota, LPS), the synthetic double stranded RNA analog [poly(I:C)], and the guanosine analog, loxoribine (LOX) directly induced both an oxidative burst and a degranulation response. Interestingly, the synthetic bacterial lipoprotein Pam3CSK4 (palmitoyl-3-cysteine-serine-lysine-4, PAM) induced degranulation, but no oxidative burst. The bacterial TLR agonists (PAM, PGN, LPS, and FGN) all induced an up-regulation of expression of mRNA of the pro-inflammatory cytokines IL-1beta, IL-6, and IL-8; whereas both poly(I:C) and LOX induced a down-regulation of these cytokine mRNAs. Stimulation of heterophils with each specific TLR agonist led to a differential increase in the phosphorylation of both p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase 1/2 (ERK 1/2) activation, but not the phosphorylation of c-Jun NH2-terminal kinase (JNK). The broad TLR expression profile in heterophils reflects their principal role as first line effector cells in avian host defense against bacterial, viral, fungal, and parasitic infections. The results demonstrate the differential involvement of TLR-induced signals in the stimulation of transduction pathways that regulate the oxygen-dependent and -independent antimicrobial defense mechanisms of avian heterophils.
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PMID:Expression and function of Toll-like receptors in chicken heterophils. 1593 35

The complement anaphylatoxins, C3a and C5a, exert their effects by binding to their respective receptors. A number of studies have implicated these proteins in human disease, yet little is known about anaphylatoxin receptor gene regulation. In this report, we demonstrate that most of the regulatory functions in the murine C3aR gene lie within 50 bp of the transcription start site. This region is critical for macrophage expression but does not have activity in a non-expressing melanoma cell line. Within this small region are putative consensus binding sites for AP-1, NF-kappaB, Ets, and GATA transcription factors. Lack of a corresponding NF-kappaB site in the human sequence and lack of DNA binding activity in macrophage nuclear extracts suggests that the NF-kappaB site is nonfunctional. Luciferase data demonstrate that the GATA site functions as a negative regulatory element in RAW 264.7 macrophages. The AP-1 and Ets sites are critical for C3aR reporter gene expression, such that when each is mutated, a significant loss of activity is observed. Furthermore, we demonstrate that these sequences cooperate to mediate both basal and LPS-induced expression of C3aR. Interestingly, EMSA analyses demonstrate that the AP-1 site binds to c-Jun, and in vivo footprinting shows a typical footprint in this site, but the Ets site does not have a "typical" Ets footprint and does not bind to Ets-1/2 proteins in RAW 264.7 extracts. These data suggest that, although the control region for C3aR is small, interaction of several transcription factors can lead to complex patterns of gene regulation.
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PMID:Characterization of the murine C3a receptor enhancer-promoter: expression control by an activator protein 1 sequence and an Ets-like site. 1611 2

In the present study, we explored the suppressive activities of 1'-acetoxychavicol acetate (ACA), auraptene, nobiletin, and zerumbone toward LPS-induced cyclooxygenase (COX)-2 mRNA expression in mouse macrophages and the underlying molecular mechanisms. Pretreatment of RAW264.7 cells with LPS led to the activation of mitogen-activated protein kinase (MAPK)s [p38, extracellular signal-regulated kinase (ERK)1/2, c-Jun NH2-terminal kinase (JNK)1/2] and Akt, together with degradation of the inhibitor of nuclear factor-kappaB (IkappaB)-alpha protein and nuclear translocation of nuclear factor (NF)-kappaB p65, and the resultant activation of activator protein (AP)-1, NF-kappaB, and cAMP-responsive element-binding protein (CREB) transcription factors. ACA abrogated ERK1/2 and JNK1/2, but not p38 MAPK, as well as the activation of those transcription factors. Although it allowed LPS-triggered phosphorylation of those MAPKs and NF-kappaB nuclear translocation, nobiletin suppressed the activation of AP-1, NF-kappaB, and CREB. Zerumbone had no effect on those transcription factors, though it attenuated COX-2 mRNA expression, suggesting that it disrupts the stabilization of COX-2 mRNA. Conversely, zerumbone significantly accelerated spontaneous COX-2 mRNA decay, the potency of which was comparable with that of SB203580, an inhibitor of p38 MAPK, whose activation has key roles in the proinflammatory mRNA stabilization processes. Because SB203580 but not zerumbone suppressed LPS-induced p38 MAPK activation, the molecular targets of zerumbone may be MAPK-activated protein kinase-2 or located downstream. However, auraptene suppressed the expression of COX-2 protein but not mRNA, implying that it targets translation. We propose that these phytochemicals are promising chemopreventive agents for inflammation-associated carcinogenesis. Their use in combination may enhance their efficacy because of their different modes of action.
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PMID:Zingiberaceous and citrus constituents, 1'-acetoxychavicol acetate, zerumbone, auraptene, and nobiletin, suppress lipopolysaccharide-induced cyclooxygenase-2 expression in RAW264.7 murine macrophages through different modes of action. 1631 59

Inflammatory responses stimulated by bacterial endotoxin LPS involve Ca2+-mediated signaling, yet the cellular sensors that determine cell fate in response to LPS remain poorly understood. We report that exposure of RAW 264.7 macrophage-like cells to LPS induces a rapid increase in CaM abundance, which is associated with the modulation of the inflammatory response. Increases in CaM abundance precede nuclear localization of key transcription factors (i.e., NF-kappaB p65 subunit, phospho-c-Jun, Sp1) and subsequent increases in the proinflammatory cytokine TNF-alpha and inducible nitric oxide synthase (iNOS). Cellular apoptosis after LPS challenge is blocked upon inhibition of iNOS activity using the pharmacological inhibitor 1400W. LPS-mediated iNOS expression and apoptosis also were inhibited by siRNA-mediated silencing of TNF induction, indicating TNF induction both precedes and is necessary for subsequent regulation of iNOS expression. Increasing the level of cellular CaM by stable transfection results in reductions in LPS-induced expression of TNF and iNOS, along with reduced activation of their transcriptional regulators and concomitant protection against apoptosis. Thus the level of CaM available for Ca2+-dependent signaling regulation plays a key role in determining the expression of the proinflammatory and proapoptotic cascade during cellular activation by LPS. These results indicate a previously unrecognized central role for CaM in maintaining cellular homeostasis in response to LPS such that, under resting conditions, cellular concentrations of CaM are sufficient to inhibit the biosynthesis of proinflammatory mediators associated with macrophage activation. Although CaM and iNOS protein levels are coordinately increased as part of the oxidative burst, limiting cellular concentrations of CaM due to association with iNOS (and other high-affinity binders) commit the cell to an unchecked inflammatory cascade leading to apoptosis.
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PMID:Functional link between TNF biosynthesis and CaM-dependent activation of inducible nitric oxide synthase in RAW 264.7 macrophages. 1642 Dec 3

In vitro studies of hepatocytes have implicated over-activation of c-Jun N-terminal kinase (JNK) signaling as a mechanism of tumor necrosis factor-alpha (TNF)-induced apoptosis. However, the functional significance of JNK activation and the role of specific JNK isoforms in TNF-induced hepatic apoptosis in vivo remain unclear. JNK1 and JNK2 function was, therefore, investigated in the TNF-dependent, galactosamine/lipopolysaccharide (GalN/LPS) model of liver injury. The toxin GalN converted LPS-induced JNK signaling from a transient to prolonged activation. Liver injury and mortality from GalN/LPS was equivalent in wild-type and jnk1-/- mice but markedly decreased in jnk2-/- mice. This effect was not secondary to down-regulation of TNF receptor 1 expression or TNF production. In the absence of jnk2, the caspase-dependent, TNF death pathway was blocked, as reflected by the failure of caspase-3 and -7 and poly(ADP-ribose) polymerase cleavage to occur. JNK2 was critical for activation of the mitochondrial death pathway, as in jnk2-/- mice Bid cleavage and mitochondrial translocation and cytochrome c release were markedly decreased. This effect was secondary to the failure of jnk2-/- mice to activate caspase-8. Liver injury and caspase activation were similarly decreased in jnk2 null mice after GalN/TNF treatment. Ablation of jnk2 did not inhibit GalN/LPS-induced c-Jun kinase activity, although activity was completely blocked in jnk1-/- mice. Toxic liver injury is, therefore, associated with JNK over-activation and mediated by JNK2 promotion of caspase-8 activation and the TNF mitochondrial death pathway through a mechanism independent of c-Jun kinase activity.
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PMID:Tumor necrosis factor-induced toxic liver injury results from JNK2-dependent activation of caspase-8 and the mitochondrial death pathway. 1657 30


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