Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diabetic retinopathy induces an inflammatory response in the retina characterized by an increase in inflammatory cytokines and the activation of microglia. The degree of microglia activation may influence the extent of retina injury following retinal metabolic stress. We have previously shown that DR rats have elevated levels of advanced glycation end products (AGEs) in their blood. We have also suggested that AGEs might be involved in microglial activation and production of tumor necrosis factor alpha (TNF alpha). In this study, we attempted to confirm that AGEs induce the release of TNF alpha from rat retinal microglia using an in vitro microglia culture system, and concurrently to explore the mediating mechanisms. AGEs increased the protein secretion and mRNA expression of TNF alpha in cultured rat retinal microglia. These effects of AGEs were primarily mediated by reactive oxygen species (ROS). Furthermore, the inhibitors for mitogen-activated protein kinases (MAPK; p38, JNK and ERK 1/2) and nuclear factor-kB (NF-kB) could significantly decrease AGEs-induced TNF alpha release. AGEs-activated microglia showed an increase of NF-kB p65 nuclear translocation. These observations indicated that pathophysiological levels of AGEs may alter rat retinal microglia function by up-regulating TNF alpha expression and release via enhanced formation of intracellular ROS. AGEs-induced ROS subsequently activates MAPK (p38, JNK and ERK1/2) and NF-kB.
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PMID:AGEs mediated expression and secretion of TNF alpha in rat retinal microglia. 1770 71

Interleukin-1 receptor-associated kinase 4 (IRAK-4) was reported to be essential for the Toll-like receptor (TLR)- and T cell receptor (TCR)-mediated signaling leading to the activation of nuclear factor kappaB (NF-kappaB). However, the importance of kinase activity of IRAK family members is unclear. In this study, we investigated the functional role of IRAK-4 activity in vivo by generating mice carrying a knockin mutation (KK213AA) that abrogates its kinase activity. IRAK-4(KN/KN) mice were highly resistant to TLR-induced shock response. The cytokine production in response to TLR ligands was severely impaired in IRAK-4(KN/KN) as well as IRAK-4(-/-) macrophages. The IRAK-4 activity was essential for the activation of signaling pathways leading to mitogen-activated protein kinases. TLR-induced IRAK-4/IRAK-1-dependent and -independent pathways were involved in early induction of NF-kappaB-regulated genes in response to TLR ligands such as tumor necrosis factor alpha and IkappaBzeta. In contrast to a previous paper (Suzuki, N., S. Suzuki, D.G. Millar, M. Unno, H. Hara, T. Calzascia, S. Yamasaki, T. Yokosuka, N.J. Chen, A.R. Elford, et al. 2006. Science. 311:1927-1932), the TCR signaling was not impaired in IRAK-4(-/-) and IRAK-4(KN/KN) mice. Thus, the kinase activity of IRAK-4 is essential for the regulation of TLR-mediated innate immune responses.
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PMID:Essential role of IRAK-4 protein and its kinase activity in Toll-like receptor-mediated immune responses but not in TCR signaling. 1748 11

Cocaine exposure results in aberrant outgrowth and decreased survival for locus coeruleus (LC), a noradrenergic population of neurons that putatively regulates attentional function; however, the underlying mechanisms for these events are not known. We previously showed that cocaine exposure in vitro activates pro-apoptotic Bax, caspase-9, and caspase-3 in LC neurons dissected from embryonic day 14 rats, implicating that apoptosis may be orchestrated via signal transduction events. In the current study in vitro, we examined upstream events to determine the role of the pro-inflammatory cytokine, tumor necrosis factor alpha (TNF-alpha), on LC signal transduction, because cocaine exposure to LC neurons triggered TNF-alpha expression at 30 min as measured by ELISA. Exposure of LC neurons to recombinant-TNF-alpha resulted in decreased metabolic activity, an indicator of reduced neuron viability [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay], and increased apoptosis (terminal deoxynucleotidyl transferase-mediated DNA nick end labeling assay). Pro-apoptotic caspase-3 was induced by cocaine starting at 30 min. Recombinant-TNF-alpha induced caspase-3 activity earlier than cocaine (15 and 20 min). The caspase-3 levels were significantly reduced when cocaine and TNF-alpha were combined with neutralizing-TNF-alpha (nTNF-alpha), respectively. Further, cocaine alone elevated phospho-p38-mitogen-activated protein kinases that persisted when combined with nTNF-alpha. However, both cocaine and TNF-alpha independently increased phospho-c-Jun NH(2)-terminal kinase and Bax levels at concurrent time periods (30 min and 1 h), and this elevation was attenuated in the presence of nTNF-alpha. These simultaneous molecular events triggered by cocaine and TNF-alpha implicate a potential apoptotic signal transduction pathway via induction of phospho-c-Jun NH(2)-terminal kinase and Bax that may lead to caspase-3 activation and apoptosis in cocaine-exposed fetal LC neurons.
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PMID:Cocaine exposure in vitro induces apoptosis in fetal locus coeruleus neurons through TNF-alpha-mediated induction of Bax and phosphorylated c-Jun NH(2)-terminal kinase. 1763 74

Mitogen-activated protein kinases (MAPK) are intracellular signaling molecules involved in cytokine synthesis. Several classes of mammalian MAPK have been identified, including extracellular signal-regulated kinase, c-jun N-terminal kinase, and p38 MAP kinase. p38alpha is a key MAPK involved in tumor necrosis factor alpha and other cytokine production, as well as enzyme induction (cyclooxygenase-2, inducible nitric oxide synthase, and matrix metalloproteinases) and adhesion molecule expression. An understanding of the broad biologic and pathophysiological roles of p38 MAPK family members has grown significantly over the past decade, as has the complexity of the signaling network leading to their activation. Downstream substrates of MAPK include other kinases (e.g., mitogen-activated protein-kinase-activated protein kinase 2) and factors that regulate transcription, nuclear export, and mRNA stability and translation. The high-resolution crystal structure of p38alpha has led to the design of selective inhibitors that have good pharmacological activity. Despite the strong rationale for MAPK inhibitors in human disease, direct proof of concept in the clinic has yet to be demonstrated, with most compounds demonstrating dose-limiting adverse effects. The role of MAPK in inflammation makes them attractive targets for new therapies, and efforts are continuing to identify newer, more selective inhibitors for inflammatory diseases.
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PMID:p38 pathway kinases as anti-inflammatory drug targets. 1772 Aug 47

Herpes simplex virus (HSV)-specific T cells are essential for viral clearance. However, T cells do not prevent HSV latent infection or reactivation, suggesting that HSV has the potential to modulate T-cell function. T-cell receptor (TCR) stimulation is a potent and specific means of activating T cells. To investigate how HSV affects T-cell function, we have analyzed how HSV affects TCR-stimulated intracellular signaling and cytokine synthesis in mock-infected and HSV-infected T cells. Mock-infected T cells stimulated through the TCR synthesized a broad range of cytokines that included the proinflammatory cytokines tumor necrosis factor alpha, gamma interferon, and interleukin-2. In contrast, HSV-infected T cells stimulated through the TCR selectively synthesized interleukin-10, a cytokine that suppresses cellular immunity and favors viral replication. To achieve selective interleukin-10 synthesis, HSV differentially affected TCR signaling pathways. HSV inhibited TCR-stimulated formation of the linker for activation of the T-cell signaling complex, and HSV inhibited TCR-stimulated NF-kappaB activation. At the same time, HSV activated the p38 and JNK mitogen-activated protein kinases as well as the downstream transcription factors ATF-2 and c-Jun. HSV did not inhibit TCR-stimulated activation of STAT3, a transcription factor involved in interleukin-10 synthesis. The activation of p38 was required for interleukin-10 synthesis in HSV-infected T cells. The ability of HSV to differentially target intracellular signaling pathways and transform an activating stimulus into an immunosuppressive response represents a novel strategy for pathogen-mediated immune modulation. Selective, TCR-stimulated interleukin-10 synthesis may play an important role in HSV pathogenesis.
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PMID:Herpes simplex virus remodels T-cell receptor signaling, resulting in p38-dependent selective synthesis of interleukin-10. 1780 1

Carbon monoxide (CO), a gaseous second messenger, arises in biological systems during the oxidative catabolism of heme by the heme oxygenase (HO) enzymes. Many biological functions of HO, such as regulation of vessel tone, smooth muscle cell proliferation, neurotransmission, and platelet aggregation, and anti-inflammatory and antiapoptotic effects have been attributed to its enzymatic product, CO. How can such diverse actions be achieved by a simple diatomic gas; can its protective effects be explained via regulation of a common signaling pathway? A number of the known signaling effects of CO depend on stimulation of soluble guanylate cyclase and/or activation of mitogen-activated protein kinases. The consequences of this activation remain unknown but appear to differ depending on cell type and circumstances. The majority of studies reporting a protective role of CO focus on pathways initiated by the pathological stimulus (e.g., lipopolysaccharide, hypoxia, balloon injury, tumor necrosis factor alpha, etc.) and its consequential modulation by CO. What has been less studied is the manner in which CO exposure alone modulates the molecular machinery of the cell so that a subsequent stress stimulus will elicit a homeostatic response as opposed to one that is chaotic and disordered. CO potentially interacts with other intracellular hemoprotein targets, although little is known about the functional significance of such interactions other then the known targets including mitochondrial oxidases, oxygen sensors, and nitric oxide synthases. The earliest response of a cell exposed to low concentrations of CO is clearly an increase in reactive oxygen species formation that we define as oxidative conditioning. This has important consequences for inflammation, proliferation, mitochondria biogenesis, and apoptosis. Within this review, we will highlight recent research on the molecular events underlying the physiologic effects of CO-which lead to cytoprotective conditioning.
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PMID:Heme oxygenase and carbon monoxide initiate homeostatic signaling. 1803 22

Many bacterial pathogens, including Staphylococcus aureus, use a variety of pore-forming toxins as important virulence factors. Staphylococcal alpha-toxin, a prototype beta-barrel pore-forming toxin, triggers the release of proinflammatory mediators and induces primarily necrotic death in susceptible cells. However, whether host factors released in response to staphylococcal infections may increase cell resistance to alpha-toxin is not known. Here we show that prior exposure to interferons (IFNs) prevents alpha-toxin-induced membrane permeabilization, the depletion of ATP, and cell death. Moreover, pretreatment with IFN-alpha decreases alpha-toxin-induced secretion of interleukin 1beta (IL-1beta). IFN-alpha, IFN-beta, and IFN-gamma specifically protect cells from alpha-toxin, whereas tumor necrosis factor alpha (TNF-alpha), IL-6, and IL-4 have no effects. Furthermore, we show that IFN-alpha-induced protection from alpha-toxin is not dependent on caspase-1 or mitogen-activated protein kinases, but requires protein synthesis and fatty acid synthase activity. Our results demonstrate that IFNs may increase cell resistance to staphylococcal alpha-toxin via the regulation of lipid metabolism and suggest that interferons play a protective role during staphylococcal infections.
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PMID:Interferons increase cell resistance to Staphylococcal alpha-toxin. 1807 Sep 1

Chlamydia pneumoniae is a common respiratory pathogen, which activates macrophages to induce inflammatory cytokines that may promote atherosclerosis. However, the antigens that induce macrophage activation have not been well defined. In the current study, three chlamydial proteins which are recognized during human infection, outer membrane protein 2 (OMP2) and two 53-kDa proteins (Cpn 0980 and Cpn 0809), were investigated to determine whether they activate macrophages and, if they do, what mechanism they use for this activation. It was shown that these three proteins could (i) induce expression of tumor necrosis factor alpha (TNF-alpha) and tissue factor and (ii) induce phosphorylation of p44/42 mitogen-activated protein kinases (MAPK) and activation of early growth response factor 1 (Egr-1). Control proteins, the N-terminal fragment of polymorphic membrane protein 8 and the thioredoxin portion of the fusion protein, had no effect on macrophages. Treatment of cells with a MEK1/2 inhibitor, U0126, dramatically reduced the phosphorylation of ERK, activation of Egr-1, and expression of TNF-alpha in macrophages treated with recombinant proteins. Toll-like receptors (TLRs) act as sensors for microbial antigens and can signal via the MAPK pathway. Chlamydial protein-induced expression of TNF-alpha was significantly reduced in macrophages lacking TLR2 or TLR4. These findings suggest that C. pneumoniae may activate macrophages through OMP2, Cpn 0980, and Cpn 0809 in addition to cHSP60 and that activation occurs via TLR2 or TLR4, Egr-1, and MAPK pathways.
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PMID:Identification and characterization of Chlamydia pneumoniae-specific proteins that activate tumor necrosis factor alpha production in RAW 264.7 murine macrophages. 1822 57

To provide a tool to investigate the mechanisms inducing and maintaining cancer-related pain and hyperalgesia, a soft tissue tumor/metastasis model was developed that is applicable in C57BL/6J wild-type and transgenic mice. We show that the experimental tumor-induced heat hyperalgesia and nociceptor sensitization were prevented by systemic treatment with the tumor necrosis factor alpha (TNFalpha) antagonist etanercept. In naive mice, exogenous TNFalpha evoked heat hyperalgesia in vivo and sensitized nociceptive nerve fibers to heat in vitro. TNFalpha enhanced the expression of the nociceptor-specific heat transducer ion channel transient receptor potential vanilloid 1 (TRPV1) and increased the amplitudes of capsaicin and heat-activated ionic currents via p38/MAP (mitogen-activated protein) kinase and PKC (protein kinase C). Deletion of the tumor necrosis factor receptor type 2 (TNFR2) gene attenuated heat hyperalgesia and prevented TRPV1 upregulation in tumor-bearing mice, whereas TNFR1 gene deletion played a minor role. We propose endogenous TNFalpha as a key player in cancer-related heat hyperalgesia and nociceptor sensitization that generates TRPV1 upregulation and sensitization via TNFR2.
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PMID:Endogenous tumor necrosis factor alpha (TNFalpha) requires TNF receptor type 2 to generate heat hyperalgesia in a mouse cancer model. 1846 60

TNF receptor-associated factor 6 (TRAF6) is an essential adaptor protein for the Interleukin-1 (IL-1) signaling pathway; however, its role in the signaling of another proinflammatory cytokine, tumor necrosis factor alpha (TNFalpha, has not been explored. Interestingly, we observed that TNFalpha-induced expression of IL-6, CXCL1 and granulocyte macrophage colony stimulating factor (GM-CSF) were significantly enhanced in TRAF6-deficient MEFs. Compared to those observed in wild-type MEFs, TNFalpha-induced IkappaB kinase (IKK) activation and IkappaBalpha degradation were enhanced in TRAF6-deficient MEFs. Also, TNFalpha-induced DNA binding activity and transcriptional activation of nuclear factor kappaB (NF-kappaB) were also augmented in TRAF6-deficient MEFs. On the other hand, TRAF6 deficiency did not affect the TNFalpha-induced activation of mitogen-activated protein (MAP) kinases, ERK, JNK, and p38. Moreover, the reintroduction of exogenous TRAF6 into TRAF6-deficient MEFs clearly suppressed TNFalpha-induced IKK activation, NF-kappaB activation and subsequent cytokine expression. In contrast, both the deletion mutant (DeltaN) and the point mutant (C70A) of TRAF6, which is defective in its ubiquitin ligase activity, failed to repress TNFalpha-induced IKK activation, NF-kappaB activation and cytokine production. Thus, these data suggest that TRAF6 negatively regulates TNFalpha-induced NF-kappaB activation through its ubiquitin ligase activity.
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PMID:TRAF6 negatively regulates TNFalpha-induced NF-kappaB activation. 1909 94


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